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 8

GLS1-mediated glutaminolysis by the MALT1/c-Jun axis contributes to excessive proliferation of and chemokine production by keratinocytes.

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GLS1-mediated glutaminolysis by the MALT1/c-Jun axis contributes to exce...
(A and B) qPCR (A) and IHC (B) for GLS1 and GLS2 expression in skin from healthy controls and patients with psoriasis (n = 12). (C–F) HaCaT cells were transfected with the control (hTRV-NC) or hTRV-GLS1. (C) Detection of transfection efficiency of hTRV-GLS1. (D) HaCaT cell proliferation was analyzed by CCK8 assay (n = 3). (E) qPCR was performed to determine the mRNA levels of chemokines secreted by HaCaT cells (n = 3). (F) Culture supernatants were collected 48 hours later and added to the lower chambers, and normal human CD4+ T cells were added to the upper chambers of Transwell plates for 2 hours. The upper chamber was removed and stained with crystal violet, and cells were counted (n = 5). (G) Representative blots for MALT1 protease activity and GLS1 and c-Jun expression in keratinocytes from mice. (H) HaCaT cells were transfected with an siRNA against c-Jun (si–c-Jun) or a control siRNA (si-NC) and then primed with MI-2 or stimulated with PMA/ionomycin (P/I) for 2 hours. Representative blots for MALT1 protease activity and GLS1 and c-Jun expression. 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, B, and D–F) was used to determine statistical significance. (*P < 0.05, **P < 0.01, ***P < 0.001).