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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

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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 7

MALT1 protease promotes GLS1-mediated glutaminolysis via c-Jun.

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MALT1 protease promotes GLS1-mediated glutaminolysis via c-Jun.
(A) Huma...
(A) Human naive CD4+ T cells were polarized into Th17 cells with the indicated treatment for 5 days. Confocal microscopy of cells stained with c-Jun antibody (green) and the DNA-binding dye DAPI (blue). Scale bars: 5 μm. Graph shows relative intensity of c-Jun expression in (n = 5). (B) Representative blots for c-Jun expression in cells from A that were restimulated with anti-CD3 and anti-CD28 antibodies followed by cycloheximide (CHX) treatment at the indicated time points (upper panel), or that were treated with MG132 or not for 12 hours. (C) ChIP for the c-Jun binding site on the proximal region of the GLS promoter (n = 3). fwd, forward; rev, reverse; TSS, transcription start site. (D) Cells in A were transduced with a concentrated retrovirus carrying hTRV–c-Jun or control (hTRV-NC). Representative blots for MALT1 protease activity following restimulation with anti-CD3 and anti-CD28 antibodies and expression of c-Jun, MALT1, c-Myc, and GLS1. (E and F) Relative mRNA (E) (n = 24) and protein (F) (n = 3 of a total of 24 samples) levels of c-Jun in psoriatic CD4+ T cells. (G–I) WT or MALT1 protease-deficient (KI) mice were painted with IMQ cream for 7 consecutive days. Clinical manifestations and H&E staining of the back skin (G) (scale bars: 100 μm). Representative blots for MALT1 protease activity and GLS1 and c-Jun expression in splenic CD4+ T cells (H) (n = 3). Acetyl-CoA concentration (n = 5) and histone acetylation of Il17a promoter regions (n = 3) in splenic CD4+ T cells (I). Data are presented as the mean ± SD and represent 1 of at least 2 independent experiments with consistent results. One-way ANOVA with Tukey’s multiple comparisons test (A) or 2-tailed, unpaired Student’s t test (E, F, and I) was used to determine statistical significance. (*P < 0.05, **P < 0.01).

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