Beclin 2 negatively regulates innate immune signaling and tumor development
Motao Zhu, … , Guangjun Nie, Rong-Fu Wang
Motao Zhu, … , Guangjun Nie, Rong-Fu Wang
Published August 31, 2020
Citation Information: J Clin Invest. 2020;130(10):5349-5369. https://doi.org/10.1172/JCI133283.
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Research Article Cell biology Inflammation

Beclin 2 negatively regulates innate immune signaling and tumor development

Abstract

Beclin 2 plays a critical role in metabolic regulation and obesity, but its functions in innate immune signaling and cancer development remain largely unknown. Here, we identified Beclin 2 as a critical negative regulator of inflammation and lymphoma development. Mice with homozygous ablation of BCL2-interacting protein 2 (Becn2) developed splenomegaly and lymphadenopathy and markedly increased ERK1/2 and NF-κB signaling for proinflammatory cytokine production. Beclin 2 targeted the key signaling kinases MEKK3 and TAK1 for degradation through an ATG9A-dependent, but ATG16L/Beclin 1/LC3–independent, autophagic pathway. Mechanistically, Beclin 2 recruited MEKK3 or TAK1 through ATG9A to form a complex (Beclin 2-ATG9A-MEKK3) on ATG9A+ vesicles upon ULK1 activation. Beclin 2 further interacted with STX5 and STX6 to promote the fusion of MEKK3- or TAK1-associated ATG9A+ vesicles to phagophores for subsequent degradation. Importantly, Becn2-deficient mice had a markedly increased incidence of lymphoma development, with persistent STAT3 activation. Myeloid-specific ablation of MEKK3 (Map3k3) completely rescued the phenotypes (splenomegaly, higher amounts of proinflammatory cytokines, and cancer incidence) of Becn2-deficient mice. Hence, our findings have identified an important role of Beclin 2 in the negative regulation of innate immune signaling and tumor development through an ATG9A-dependent, but ATG16L/Beclin 1/LC3–independent, autophagic pathway, thus providing a potential target for the treatment of inflammatory diseases and cancer.

Authors

Motao Zhu, Guangtong Deng, Peng Tan, Changsheng Xing, Cuiping Guan, Chongming Jiang, Yinlong Zhang, Bo Ning, Chaoran Li, Bingnan Yin, Kaifu Chen, Yuliang Zhao, Helen Y. Wang, Beth Levine, Guangjun Nie, Rong-Fu Wang

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Figure 1

Splenomegaly and lymphadenopathy in Becn2-deficient mice.

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Splenomegaly and lymphadenopathy in Becn2-deficient mice. (A) Real-time ...
(A) Real-time PCR (RT-PCR) analysis of human Beclin 2 expression in different tissues and cells. The mRNA levels of BECN2 in different tissues or cells were normalized to the mRNA levels of the GAPDH gene. Data are plotted as mean ± SEM and are representative of at least 3 independent experiments. (B) Sizes of spleens (upper) and lymph nodes (LNs, lower) from Becn2-KO and WT mice (n = 4 per group). (C) H&E staining of spleen and lymph nodes of Becn2-KO and WT mice. Images are representative of 4 mice in each group. (D) Total numbers of splenocytes and lymphocytes from lymph nodes counted from 6- to 8-week-old Becn2-KO and WT mice (n = 6 mice per group). (E and F) Representative flow cytometry plots and quantification of 6- to 8-week-old B220+ and CD3+ cell populations in spleens (E) and lymph nodes (F) (n = 8 mice per group). Statistical differences between groups were calculated using Student’s unpaired t test. **P < 0.01.