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Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease
Kun Yang, … , Luis A. Garza, Nan Yan
Kun Yang, … , Luis A. Garza, Nan Yan
Published January 18, 2022
Citation Information: J Clin Invest. 2022;132(2):e146176. https://doi.org/10.1172/JCI146176.
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Research Article Autoimmunity Metabolism Article has an altmetric score of 4

Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease

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Abstract

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.

Authors

Kun Yang, Jie Han, Mayumi Asada, Jennifer G. Gill, Jason Y. Park, Meghana N. Sathe, Jyothsna Gattineni, Tracey Wright, Christian A. Wysocki, M. Teresa de la Morena, Luis A. Garza, Nan Yan

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Figure 6

mTORC1 inhibitor rapamycin ameliorates disease pathology in postnatal whole-body inducible Skiv2l knockout mice.

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mTORC1 inhibitor rapamycin ameliorates disease pathology in postnatal wh...
(A) A schematic diagram showing experiment design of rapamycin treatment by intraperitoneal injection in iSkiv2l–/– mice and Skiv2lfl/fl controls. (B and C) Representative images of iSkiv2l–/– and Skiv2lfl/fl mice treated with rapamycin (Rapa, 8 mg/kg body weight, i.p.) or vehicle (veh) for 4 weeks. Quantification of area with lesion on ventral skin is shown on right bar graph (C). n = 6 per group. Two-sided Student’s t test, ***P < 0.001. (D) H&E staining of iSkiv2l–/– and Skiv2lfl/fl mouse dorsal skin after treatment with rapamycin or vehicle (as in B). Quantification of epidermal thickness is showing on the right bar graph. n = 6 mice per group. Two-way ANOVA with post hoc Tukey’s multiple comparisons test, ***P < 0.001. (E and F) Fluorescence immunohistochemistry analysis of p-S6 ribosomal protein (S235/236) (E) and proliferation marker Ki67 (F) of iSkiv2l–/– and Skiv2lfl/fl mouse dorsal skin after treatment with rapamycin or vehicle (as in B). White arrows in F denote Ki67-positive cells. Scale bar: 50 μm. (G) T cell proliferation analysis by the CFSE dilution assay. iSkiv2l–/– and Skiv2lfl/fl splenic CD8+ T cells were stained with CFSE then stimulated with anti-CD3 and anti-CD28 (3 μg/mL) in the presence of rapamycin or vehicle DMSO. One-way ANOVA with post hoc Tukey’s multiple comparisons test, ***P < 0.001. (H) Intracellular IFN-γ staining of iSkiv2l–/– and Skiv2lfl/fl splenic CD8+ T cells stimulated with anti-CD3 and anti-CD28 (3 μg/mL) in the presence of rapamycin or vehicle DMSO. One-way ANOVA with post hoc Tukey’s multiple comparisons test, *P < 0.05, **P < 0.01.

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