The Francis Crick Institute, London NW1 1AT, U.K.
Institute of Immunity and Transplantation, University College London, London NW3 2PP, U.K.
Biochem J. 2024 Sep 18;481(18):1143-1171. doi: 10.1042/BCJ20240058.
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.
罕见的 CARD14 基因突变通过诱导 CARD14-BCL10-MALT1 复合物激活 NF-κB 和 MAP 激酶来促进银屑病的发生。在此，描述了高外显率的 CARD14E138A 改变的下游信号机制。除了 BCL10 和 MALT1 之外，CARD14E138A 还与几种在先天免疫信号中起重要作用的蛋白质相互作用。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 的泛素化，对于 NF-κB 和 MAP 激酶的激活是必不可少的。相比之下，与银屑病的发展都有遗传关联的泛素结合蛋白 A20 和 ABIN1 通过诱导 CARD14E138A 周转，负调控信号。CARD14E138A 定位于早期内体，并与 AP2 衔接复合物相关。AP2 功能对于 CARD14E138A 激活 mTOR 复合物 1（mTORC1）是必需的，这刺激角质形成细胞代谢，但对于 NF-κB 或 MAP 激酶的激活不是必需的。此外，雷帕霉素改善了 CARD14E138A 诱导的角质形成细胞增殖和表皮棘皮症在小鼠中，这表明阻断 mTORC1 可能对 CARD14 依赖性银屑病具有治疗益处。
