GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis
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
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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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 9

Schematic illustration of GLS1-mediated glutaminolysis contributing to the pathogenesis of psoriasis.

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Schematic illustration of GLS1-mediated glutaminolysis contributing to t...
In patients with psoriasis, consecutive activation of MALT1 protease stabilizes c-Jun, which binds to the GLS1 promoter region and increases expression of GLS1, thus leading to aberrant glutaminolysis. GLS1-mediated glutaminolysis augments intracellular acetyl-CoA via the TCA cycle, which contributes to histone H3 acetylation of the IL17A promoter and RORC transcriptional activity, thereby aggravating T17 cell differentiation in psoriasis. On the other hand, IL-17A/MALT1/c-Jun axis–induced GLS1-mediated glutaminolysis also enhances the proliferation of and chemokine secretion by keratinocytes, which increases the recruitment of activated T cells in skin lesions. Together, the effects of the aberrant MALT1/c-Jun/GLS1 pathway on CD4+ and γδ T cells, together with keratinocytes contribute to the formation of psoriatic skin lesions. KCs, keratinocytes.