Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease.
Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease.
复制标题
细胞质RNA质量控制失败涉及mTORC 1介导的自身炎症性疾病。
DOI：
10.1172/jci146176
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发表时间：
2022-01-18
期刊：
影响因子：
--
通讯作者：
Yan N
中科院分区：
文献类型：
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作者：
Yang K;Han J;Asada M;Gill JG;Park JY;Sathe MN;Gattineni J;Wright T;Wysocki CA;de la Morena MT;Garza LA;Yan N
先天的核酸代谢错误常常引起核酸感应通路的异常激活，从而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，被认为是防止自我RNA介导的干扰素（IFN）反应所必需的。在这里，我们证明了SKIV2L在哺乳动物中的生理功能。我们发现小鼠Skiv2l缺乏以独立于IFN的细胞内在方式破坏表皮和T细胞的稳态。skiv2l缺陷小鼠出现皮肤炎症和毛发异常，在skiv2l缺陷患者中也观察到这一点。Skiv2l的表皮特异性缺失导致角化细胞过度增殖和表皮分层破坏，导致皮肤屏障受损，没有明显的IFN激活。此外，skiv21缺陷T细胞慢性过度激活，这些T细胞攻击病变皮肤和毛囊。在机制上，SKIV2L缺失激活了角质形成细胞和T细胞中的mTORC1通路。全身和局部雷帕霉素治疗skiv2l缺陷小鼠均可改善表皮增生和皮肤炎症。总之，我们证明了mTORC1，一种经典的营养传感器，也感知细胞质RNA质量控制失败并驱动自身炎症性疾病。我们还提出skiv2l相关的trichoho肝肠综合征（THES）作为一种新的肿瘤，西罗莫司可能是一种有希望的治疗方法。
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.