CARD14 signalosome formation is associated with its endosomal relocation and mTORC1-induced keratinocyte proliferation.

IF 4.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemical Journal Pub Date : 2024-09-18 DOI:10.1042/BCJ20240058
Paul A O'Sullivan, Aigerim Aidarova, Inna S Afonina, Joan Manils, Teresa L M Thurston, Rachael Instrell, Michael Howell, Stefan Boeing, Sashini Ranawana, Melanie B Herpels, Riwia Chetian, Matilda Bassa, Helen Flynn, David Frith, Ambrosius P Snijders, Ashleigh Howes, Rudi Beyaert, Anne M Bowcock, Steven C Ley
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引用次数: 0

Abstract

Rare mutations in CARD14 promote psoriasis by inducing CARD14-BCL10-MALT1 complexes that activate NF-κB and MAP kinases. Here, the downstream signalling mechanism of the highly penetrant CARD14E138A alteration is described. In addition to BCL10 and MALT1, CARD14E138A associated with several proteins important in innate immune signalling. Interactions with M1-specific ubiquitin E3 ligase HOIP, and K63-specific ubiquitin E3 ligase TRAF6 promoted BCL10 ubiquitination and were essential for NF-κB and MAP kinase activation. In contrast, the ubiquitin binding proteins A20 and ABIN1, both genetically associated with psoriasis development, negatively regulated signalling by inducing CARD14E138A turnover. CARD14E138A localized to early endosomes and was associated with the AP2 adaptor complex. AP2 function was required for CARD14E138A activation of mTOR complex 1 (mTORC1), which stimulated keratinocyte metabolism, but not for NF-κB nor MAP kinase activation. Furthermore, rapamycin ameliorated CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice, suggesting that blocking mTORC1 may be therapeutically beneficial in CARD14-dependent psoriasis.

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CARD14 信号体的形成与其内表皮迁移和 mTORC1 诱导的角膜细胞增殖有关。
CARD14 的罕见突变可诱导 CARD14-BCL10-MALT1 复合物激活 NF-kB 和 MAP 激酶,从而诱发银屑病。本文描述了高渗透性 CARD14E138A 变异的下游信号机制。除 BCL10 和 MALT1 外,CARD14E138A 还与先天性免疫信号传导过程中的几个重要蛋白相关。与 M1 特异性泛素 E3 连接酶 HOIP 和 K63 特异性泛素 E3 连接酶 TRAF6 的相互作用促进了 BCL10 泛素化,并且对 NF-kB 和 MAP 激酶的激活至关重要。相反,泛素结合蛋白 A20 和 ABIN1(两者都与牛皮癣的发生有遗传关系)通过诱导 CARD14E138A 的周转对信号进行负向调节。CARD14E138A 定位于早期内体,并与 AP2 适配复合物相关联。CARD14E138A 激活 mTOR 复合物 1(刺激角质形成细胞的新陈代谢)需要 AP2 的功能,但 NF-kB 和 MAP 激酶的激活则不需要 AP2 的功能。此外,雷帕霉素能改善CARD14E138A诱导的小鼠角质细胞增殖和表皮棘皮症,这表明阻断mTORC1可能对CARD14依赖性银屑病有治疗作用。
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来源期刊
Biochemical Journal
Biochemical Journal 生物-生化与分子生物学
CiteScore
8.00
自引率
0.00%
发文量
255
审稿时长
1 months
期刊介绍: Exploring the molecular mechanisms that underpin key biological processes, the Biochemical Journal is a leading bioscience journal publishing high-impact scientific research papers and reviews on the latest advances and new mechanistic concepts in the fields of biochemistry, cellular biosciences and molecular biology. The Journal and its Editorial Board are committed to publishing work that provides a significant advance to current understanding or mechanistic insights; studies that go beyond observational work using in vitro and/or in vivo approaches are welcomed. Painless publishing: All papers undergo a rigorous peer review process; however, the Editorial Board is committed to ensuring that, if revisions are recommended, extra experiments not necessary to the paper will not be asked for. Areas covered in the journal include: Cell biology Chemical biology Energy processes Gene expression and regulation Mechanisms of disease Metabolism Molecular structure and function Plant biology Signalling
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