GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis
| العنوان: | GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis |
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| المؤلفون: | Peng Li, Leqing Zhu, Liehua Deng, Zhizhong Li, Hua Zhang, Yueqi Song, Xichun Xia, Jianlei Hao, Xiao Wang, Chengbin Guo, Zhinan Yin, Guangchao Cao, Yixia Tian, Wei Zhou, Yunfei Gao, Jingxiang Zhong, Guodong Sun |
| المصدر: | J Clin Invest |
| بيانات النشر: | American Society for Clinical Investigation, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Adult, Keratinocytes, Male, 0301 basic medicine, Chemokine, Glutamine, Cellular differentiation, medicine.disease_cause, Autoimmunity, Mice, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Glutaminase, T-Lymphocyte Subsets, Psoriasis, medicine, Animals, Humans, RNA, Messenger, Histone H3 acetylation, Aged, Mice, Knockout, Glutaminolysis, biology, Chemistry, Interleukin-17, Cell Differentiation, General Medicine, Middle Aged, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, MALT1, 030104 developmental biology, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Case-Control Studies, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Th17 Cells, Female, IL17A, Metabolic Networks and Pathways, Research Article |
| الوصف: | 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. |
| تدمد: | 1558-8238 0021-9738 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d1f6d904955d64d82e287033ac565778Test https://doi.org/10.1172/jci129269Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d1f6d904955d64d82e287033ac565778 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15588238 00219738 |
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