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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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Project description:Accumulated evidence demonstrated that long non-coding RNAs (lncRNAs) play a pivotal role in tumorigenesis. However, it is still largely unknown how these lncRNAs were regulated by small ncRNAs, such as microRNAs (miRNAs), at the post-transcriptional level. We here use lncRNA HOTTIP as an example to study how miRNAs impact lncRNAs expression and its biological significance in hepatocellular carcinoma (HCC). LncRNA HOTTIP is a vital oncogene in HCC, one of the deadliest cancers worldwide. In the current study, we identified miR-192 and miR-204 as two microRNAs (miRNAs) suppressing HOTTIP expression via the Argonaute 2 (AGO2)-mediated RNA interference (RNAi) pathway in HCC. Interaction between miR-192 or miR-204 and HOTTIP were further confirmed using dual luciferase reporter gene assays. Consistent with this notion, a significant negative correlation between these miRNAs and HOTTIP exists in HCC tissue specimens. Interestingly, the dysregulation of the three ncRNAs was associated with overall survival of HCC patients. In addition, the posttranscriptional silencing of HOTTIP by miR-192, miR-204 or HOTTIP siRNAs could significantly suppress viability of HCC cells. On the contrary, antagonizing endogenous miR-192 or miR-204 led to increased HOTTIP expression and stimulated cell proliferation. In vivo mouse xenograft model also support the tumor suppressor role of both miRNAs. Besides the known targets (multiple 5' end HOX A genes, i.e. HOXA13), glutaminase (GLS1) was identified as a potential downstream target of the miR-192/-204-HOTTIP axis in HCC. Considering glutaminolysis as a crucial hallmark of cancer cells and significantly inhibited cell viability after silencingGLS1, we speculate that the miR-192/-204-HOTTIP axis may interrupt HCC glutaminolysis through GLS1 inhibition. These results elucidate that the miR-192/-204-HOTTIP axis might be an important molecular pathway during hepatic cell tumorigenesis. Our data in clinical HCC samples highlight miR-192, miR-204 and HOTTIP with prognostic and potentially therapeutic implications.

Project description:BackgroundSecretory leukocyte protease inhibitor (SLPI), a ~12 kDa protein is an important regulator of innate and adaptive immunity and a component of tissue regenerative programmes. SLPI expression is markedly elevated in chronically inflamed skin, including that of individuals suffering from psoriasis. However, the role of SLPI in these diseases remains elusive.ObjectivesThe poor understanding of the early stages of the development of psoriasis is a major obstacle to successful intervention in the skin pathology. We hypothesized that SLPI and peripheral nerves that might be activated early in the progression of the disease likely form a functional relationship to maintain skin barrier homeostasis and respond to a variety of threats.MethodsWe used skin biopsies of healthy donors and individuals with psoriasis to show expression pattern of SLPI. A role of SLPI in psoriasis was mechanistically assessed using SLPI-deficient mice and an imiquimod (IMQ)-induced experimental model of psoriasis.ResultsWe show that mice lacking SLPI had exaggerated skin alterations that extended beyond the treatment site in an imiquimod-induced psoriasis. The spatiotemporally distinct skin responses in SLPI-deficient mice, compared to their wild-type littermates, resulted from a compromised skin barrier function that manifested itself in heightened transepidermal water loss through the larger skin area surrounding the IMQ-challenged skin. The increased pathogenic skin changes in the absence of SLPI were reversible through pharmacological treatment that blocks a nerve-reflex arc.ConclusionsTogether, these data indicate that SLPI plays a protective role in psoriasis through preventing skin dryness, inherent in the pathogenesis of psoriasis and that this SLPI action depends on neuronal input operating in a reflex manner. These findings reveal a previously unrecognized mechanism that maintains cutaneous homeostasis, which involves a crosstalk between the nervous system and a protein anatomically poised to fortify the epidermal permeability barrier.

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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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