Inborn errors of nucleic acid metabolism often cause aberrant activation of nucleic acid sensing pathways, leading to autoimmune or autoinflammatory diseases. The SKIV2L RNA exosome is cytoplasmic RNA degradation machinery that was thought to be essential for preventing the self-RNA–mediated interferon (IFN) response. Here, we demonstrate the physiological function of SKIV2L in mammals. We found that Skiv2l deficiency in mice disrupted epidermal and T cell homeostasis in a cell-intrinsic manner independently of IFN. Skiv2l-deficient mice developed skin inflammation and hair abnormality, which were also observed in a SKIV2L-deficient patient. Epidermis-specific deletion of Skiv2l caused hyperproliferation of keratinocytes and disrupted epidermal stratification, leading to impaired skin barrier with no appreciable IFN activation. Moreover, Skiv2l-deficient T cells were chronically hyperactivated and these T cells attacked lesional skin as well as hair follicles. Mechanistically, SKIV2L loss activated the mTORC1 pathway in both keratinocytes and T cells. Both systemic and topical rapamycin treatment of Skiv2l-deficient mice ameliorated epidermal hyperplasia and skin inflammation. Together, we demonstrate that mTORC1, a classical nutrient sensor, also senses cytoplasmic RNA quality control failure and drives autoinflammatory disease. We also propose SKIV2L-associated trichohepatoenteric syndrome (THES) as a new mTORopathy for which sirolimus may be a promising therapy.

中文翻译：

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细胞质 RNA 质量控制失败与 mTORC1 介导的自身炎症性疾病有关

核酸代谢的先天性错误常常导致核酸传感通路的异常激活，导致自身免疫或自身炎症性疾病。SKIV2L RNA 外泌体是细胞质 RNA 降解机制，被认为对于防止自身 RNA 介导的干扰素 (IFN) 反应至关重要。在这里，我们展示了 SKIV2L 在哺乳动物中的生理功能。我们发现小鼠中的Skiv2l缺陷以细胞固有的方式破坏了表皮和 T 细胞的稳态，而与 IFN 无关。Skiv2l 缺陷小鼠出现皮肤炎症和毛发异常，这也在SKIV2L 缺陷患者中观察到。Skiv2l的表皮特异性缺失导致角质形成细胞过度增殖并破坏表皮分层，导致皮肤屏障受损而没有明显的IFN活化。此外，Skiv2l 缺陷型 T 细胞长期过度活化，这些 T 细胞攻击病变皮肤和毛囊。从机制上讲，SKIV2L 缺失激活了角质形成细胞和 T 细胞中的 mTORC1 通路。Skiv2l缺陷小鼠的全身和局部雷帕霉素治疗都改善了表皮增生和皮肤炎症。我们一起证明了 mTORC1，一种经典的营养传感器，也能感知细胞质 RNA 质量控制失败并驱动自身炎症性疾病。我们还建议使用 SKIV2L-相关的毛肝肠综合征 (THES) 作为一种新的 mTORopathy，西罗莫司可能是一种有前途的治疗方法。