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ResearchIn-Press PreviewCell biologyMetabolism Open Access | 10.1172/JCI186258

Multi-omic analysis reveals a key BCAT1 role in mTOR activation by B-cell receptor and TLR9

Rui Guo,1 Yizhe Sun,2 Matthew Y. Lim,3 Hardik Shah,4 Joao A. Paulo,3 Rahaman A. Ahmed,5 Weixing Li,6 Yuchen Zhang,2 Haopeng Yang,7 Liang Wei Wang,2 Daniel Strebinger,8 Nicholas A. Smith,2 Meng Li,9 Merrin Man Long Leong,2 Michael Lutchenkov,2 Jin-Hua Liang,2 Zhixuan Li,2 Yin Wang,2 Rishi Puri,10 Ari Melnick,9 Michael R. Green,7 John M. Asara,11 Adonia E. Papathanassiu,6 Duane R. Wesemann,12 Steven P. Gygi,3 Vamsi K. Mootha,13 and Benjamin E. Gewurz1

1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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1Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, Boston, United States of America

2Division of Infectious Diseases, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America

3Department of Cell Biology, Harvard Medical School, Boston, United States of America

4Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, United States of America

5Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women's Hospital, Boston, United States of America

6Ergon Pharmaceuticals, Silver Spring, United States of America

7Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, United States of America

8Broad Institute of Harvard and MIT, Cambridge, United States of America

9Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, United States of America

10Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, United States of America

11Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, United States of America

12Department of Medicine, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States of America

13Center for Integrated Solutions in Infectious Disease, Broad Institute, Cambridge, United States of America

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Published September 9, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI186258.
Copyright © 2025, Guo et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 9, 2025 - Version history
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Abstract

B-lymphocytes play major adaptive immune roles, producing antibody and driving T-cell responses. However, how immunometabolism networks support B-cell activation and differentiation in response to distinct receptor stimuli remains incompletely understood. To gain insights, we systematically investigated acute primary human B-cell transcriptional, translational and metabolomic responses to B-cell receptor (BCR), Toll-like receptor 9 (TLR9), CD40-ligand (CD40L), interleukin-4 (IL4) or combinations thereof. T-independent BCR/TLR9 co-stimulation, which drives malignant and autoimmune B-cell states highly induced the transaminase branched chain amino acid transaminase 1 (BCAT1), which localized to lysosomal membranes to support branched chain amino acid synthesis and mechanistic target of rapamycin complex 1 (mTORC1) activation. BCAT1 inhibition blunted BCR/TLR9, but not CD40L/IL4-triggered B-cell proliferation, IL10 expression and BCR/TLR pathway-driven lymphoma xenograft outgrowth. These results provide a valuable resource, reveal receptor-mediated immunometabolism remodeling to support key B-cell phenotypes and identify BCAT1 as an activated B-cell therapeutic target.

Graphical Abstract
graphical abstract
Supplemental material

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View Supplementary Table S1. Transcriptomic, proteomic, and metabolomics analysis of human primary B cells simulated by 10 indicated conditions for 24 hours. Related to Figure 1-3 and S1-4.

View Supplementary Table S2. Metabolomic analysis of ERG245 vs vehicle treated Rael cells expressing sgRNAs targeting control or BCAT1 and stimulated by αIgM+CpG for 24h. Related to Figure S8.

View Supplementary Table S3. RNAseq analysis of primary B-cells electroporated with Cas9 RNPs loaded with control or BCAT1 sgRNAs and stimulated by αIgM+CpG for 24h. Related to Figure 3, S11.

View Supplementary Table S4. Ion intensities of 13C carbon labeled metabolites in BCAA and TCA metabolism. Related to Figure 4.

View Supplementary Table S5. Metabolomic analysis of ERG245 vs vehicle treated primary B-cells stimulated by αIgM+CpG for 24h. Related to Figure 4.

View Supplementary Table S6. Tandem-mass-tag protein abundances in immunopurified lysosomes from Rael Lyso-IP cell unstimulated or stimulated by αIgM+CpG. Raw data was median normalized. Related to Figure 5.

View Supplementary Table S7. BCAAs and BCKA ion intensities in whole cell vs lysosomes immunopurified from Rael Lyso-IP cells unstimulated or stimulated by αIgM+CpG. Related to Figure 5. Tandem-mass-tag protein abundances in unstimulated, αIgM+CpG stimulated human naïve B cells or in HBL1 DLBCL. Related to Figure 6.

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