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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 ?? T17 (IL-17A-producing ?? 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 ?? 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 ?? 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.

SUBMITTER: Xia X

PROVIDER: S-EPMC7524468 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis.

Xia Xichun X Cao Guangchao G Sun Guodong G Zhu Leqing L Tian Yixia Y Song Yueqi Y Guo Chengbin C Wang Xiao X Zhong Jingxiang J Zhou Wei W Li Peng P Zhang Hua H Hao Jianlei J Li Zhizhong Z Deng Liehua L Yin Zhinan Z Gao Yunfei Y

The Journal of clinical investigation 20201001 10

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 ...[more]

PMID: 32831293

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Dataset Information

GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis.

Publications

GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis.

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