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 2

GLS1-mediated glutaminolysis favors human Th17 differentiation in psoriasis.

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GLS1-mediated glutaminolysis favors human Th17 differentiation in psoria...
(A) Human naive CD4+ T cells were polarized under the indicated conditions in vitro for 5 days. Relative mRNA and protein expression levels of GLS1 and GLS2 (n = 6). (B and C) Vehicle-, BPTES-, or CB-839–treated human naive CD4+ T cells were polarized into Th17 cells for 5 days. (B) Flow cytometry and statistical analysis for the percentage of Th17 cells (n = 6). (C) Relative mRNA (n = 4) and protein (n = 3) levels of IL-17A and IL-17F. (D and E) Human naive CD4+ T cells were transduced with retrovirus carrying hTRV-GLS1 or control and then polarized into Th17 cells for 5 days. (D) Flow cytometry and statistical analysis for the percentage of Th17 cells (n = 6). (E) Relative mRNA and protein levels of IL-17A and IL-17F (n = 3). (F and G) Human naive CD4+ T cells were treated with vehicle or BPTES and polarized into Th17 cells for 3 days, followed by either no treatment or supplementation with glutamate for another 2 days. (F) Flow cytometry and statistical analysis for the percentage of Th17 cells (n = 6). (G) Relative mRNA expression and protein levels of IL-17A and IL-17F (n = 3). Data are presented as the mean ± SD and represent 1 of at least 2 independent experiments with consistent results. A 1-way ANOVA with Tukey’s multiple comparisons test (A–C, F, and G) or 2-tailed, unpaired Student’s t test (D and E) was used to determine statistical significance (*P < 0.05, **P < 0.01, ***P < 0.001).