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.

中文翻译：

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CARD14 信号体的形成与其内体重新定位和 mTORC1 诱导的角质形成细胞增殖有关。


CARD14 中的罕见突变通过诱导激活 NF-κB 和 MAP 激酶的 CARD14-BCL10-MALT1 复合物来促进银屑病。在这里，描述了高渗透性 CARD14E138A 改变的下游信号机制。除了 BCL10 和 MALT1 之外，CARD14E138A 还与先天免疫信号传导中重要的几种蛋白相关。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，对 NF-κB 和 MAP 激酶激活至关重要。相比之下，泛素结合蛋白 A20 和 ABIN1 均在遗传上与银屑病发展相关，通过诱导CARD14E138A周转来负向调节信号传导。CARD14E138A定位于早期内体，并与 AP2 接头复合物相关。AP2 功能是 mTOR 复合物 1 （mTORC1） CARD14E138A激活所必需的，它刺激角质形成细胞代谢，但不是 NF-κB 或 MAP 激酶激活所必需的。此外，雷帕霉素改善了CARD14E138A诱导的小鼠角质形成细胞增殖和表皮棘皮症，表明阻断 mTORC1 可能对 CARD14 依赖性银屑病的治疗有益。