Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease.

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

doi:10.1172/jci146176

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.

Highlights

Recognition of microbial nucleic acids by the innate immune system and activation of the type I interferon (IFN) response are fundamental mechanisms of host defense against infection
We did not observe significant inflammation in duodenum, colon, liver, or kidney of iSkiv2l–/– mice, nor any changes in cytokines and chemokines in the serum compared with Skiv2lfl/fl littermate controls (Supplemental Figure 2, E and F), suggesting that the inflammation is restricted to the skin even though the Skiv2l gene is deleted in the whole body
Aicardi-Goutières syndrome mutations in RNase H2 or in adenosine deaminase acting on RNA 1 (ADAR1) invoke innate immune sensing of self-nucleic acids (DNA or RNA), leading to type I IFN signaling and systemic inflammation [13]

Summary

RESEARCH ARTICLE

Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease. Inborn errors of nucleic acid metabolism often cause aberrant activation of nucleic acid sensing pathways, leading to autoimmune or autoinflammatory diseases. We found that Skiv2l deficiency in mice disrupted epidermal and T cell homeostasis in a cell-intrinsic manner independently of IFN. Epidermis-specific deletion of Skiv2l caused hyperproliferation of keratinocytes and disrupted epidermal stratification, leading to impaired skin barrier with no appreciable IFN activation. 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. We demonstrate that mTORC1, a classical nutrient sensor, senses cytoplasmic RNA quality control failure and drives autoinflammatory disease. We propose SKIV2L-associated trichohepatoenteric syndrome (THES) as a new mTORopathy for which sirolimus may be a promising therapy

Introduction

Results

Discussion

None detected

Author contributions