GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis
Xichun Xia, … , Zhinan Yin, Yunfei Gao
Xichun Xia, … , Zhinan Yin, Yunfei Gao
Published August 24, 2020
Citation Information: J Clin Invest. 2020;130(10):5180-5196. https://doi.org/10.1172/JCI129269.
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Research Article Autoimmunity Dermatology

GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis

Abstract

Psoriasis is a severe disease associated with the disturbance of metabolism and inflammation, but the molecular mechanisms underlying these aspects of psoriasis pathology are poorly understood. Here, we report that glutaminase 1–mediated (GLS1-mediated) glutaminolysis was aberrantly activated in patients with psoriasis and in psoriasis-like mouse models, which promoted Th17 and γδ T17 (IL-17A–producing γδ T) cell differentiation through enhancement of histone H3 acetylation of the Il17a promoter, thereby contributing to the immune imbalance and development of psoriasis. We further demonstrate that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) protease was constitutively active in psoriatic CD4+ and γδ T cells, thereby supporting GLS1 expression by stabilizing c-Jun, which directly binds to the GLS1 promoter region. Blocking the activity of either GLS1 or MALT1 protease resolved Th17 and γδ T17 cell differentiation and epidermal hyperplasia in the psoriasis-like mouse models. Finally, IL-17A enhanced GLS1 expression via the MALT1/cJun pathway in keratinocytes, resulting in hyperproliferation of and chemokine production by keratinocytes. Our findings identify the role of the MALT1/cJun/GLS1/glutaminolysis/H3 acetylation/T17 axis in psoriasis pathogenesis and reveal potential therapeutic targets for this disease.

Authors

Xichun Xia, Guangchao Cao, Guodong Sun, Leqing Zhu, Yixia Tian, Yueqi Song, Chengbin Guo, Xiao Wang, Jingxiang Zhong, Wei Zhou, Peng Li, Hua Zhang, Jianlei Hao, Zhizhong Li, Liehua Deng, Zhinan Yin, Yunfei Gao

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Figure 6

MALT1 protease is consecutively activated and initiates aberrant GLS1-mediated glutaminolysis in psoriasis.

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MALT1 protease is consecutively activated and initiates aberrant GLS1-me...
(A) Peripheral CD4+ T cells were collected from healthy donors and patients with psoriasis. Representative blots for the expression level and protease activity of MALT1 (cleavage of CYLD to CYLD-Ct, BCL-10) in CD4+ T cells are shown (n = 3 of a total of 24 samples). CYLD-FL, full-length CYLD; CYLD-Ct, cleaved CYLD. (B–G) Human naive CD4+ T cells subjected to the indicated treatments were polarized into Th17 cells for 5 days. (B) Representative blots show the protein levels of key metabolic enzymes. (C) Consumption of glutamine at the indicated time points. “Medium” refers to glutamine natural degradation (n = 3). (D and E) GLS1 activity (D) (n = 8) and glutamate concentration (E) (n = 5) were measured. (F) Cells were collected to detect the OCR using an extracellular flux analyzer. Cumulative data for the calculated spare respiratory capacity (SRC) are shown (n = 4). Oligo, oligomycin; FCCP, carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone; R/A, rotenone and antimycin. (G) Percentage of Th17 cells detected by flow cytometry and statistical analysis (n = 10). (H and I) Protein expression of GLS1 (H) and relative mRNA expression of IL17A, IL17F, IFNG, and IL4 (I) (n = 8) in human psoriatic CD4+ T cells treated with MI-2 for 48 hours. Data are presented as the mean ± SD and represent 1 of at least 2 independent experiments with consistent results. A 2-tailed, unpaired Student’s t test (A) or 1-way ANOVA with Tukey’s multiple comparisons test (C–G and I) was used to determine statistical significance. (*P < 0.05, **P < 0.01, ***P < 0.001).