Sensing of RNA stress by mTORC1 drives autoinflammation
Min Ae Lee-Kirsch
Min Ae Lee-Kirsch
Published January 18, 2022
Citation Information: J Clin Invest. 2022;132(2):e156119. https://doi.org/10.1172/JCI156119.
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Commentary

Sensing of RNA stress by mTORC1 drives autoinflammation

Abstract

Loss-of-function mutations in SKIV2L underlie trichohepatoenteric syndrome (THES2), a rare inborn error of immunity characterized by diarrhea, skin lesions, brittle hair, and immunodeficiency. SKIV2L is part of a multiprotein complex required for exosome-mediated RNA surveillance through RNA decay. In this issue of the JCI, Yang et al. delineate a mechanism underlying autoinflammatory skin disease in Skiv2l-deficient mice. Thus, a lack of SKIV2L activates mTORC1 signaling in keratinocytes and T cells, impeding skin barrier integrity and T cell homeostasis. Interestingly, treatment with the mTOR inhibitor rapamycin improves skin symptoms in Skiv2l-deficient mice, suggesting a possible therapeutic avenue for patients with THES2.

Authors

Min Ae Lee-Kirsch

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Figure 1

A model for mTORC1 signaling in SKIV2L deficiency that leads to uncontrolled proliferation and immune activation.

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A model for mTORC1 signaling in SKIV2L deficiency that leads to uncontro...
(A) The turnover and quality control of ribosome-associated mRNA are controlled by the cytoplasmic RNA exosome, which acts as a molecular shredder by degrading mRNA from the 3′ end. The RNA exosome is assisted by the SKI complex. The SKIV2L helicase unwinds RNA and, together with the TPR motif–containing protein TTC37 and two subunits of the WD-repeat protein WDR61, initiates ribonucleolytic degradation. The mTORC1 complex senses nutrient deprivation, which induces activation of downstream targets S6K and 4E-BP1 by phosphorylation. mTORC1 signaling promotes a broad range of anabolic processes, including cell growth and proliferation, which require a sufficient supply of deoxyribonucleotides for DNA synthesis. (B) Aberrant mTORC1 signaling in SKIV2L deficiency may be triggered by sensing changes in cellular concentrations of deoxyribonucleotides, which are produced from ribonucleotides by the action of ribonucleotide reductase (RNR). Unabated mTORC1 activity in keratinocytes and T cells leads to hyperproliferation with secondary inflammatory responses. Rapamycin inhibits the protein kinase mTOR, core component of the mTORC1 complex, and may therefore be of therapeutic benefit in patients with SKIV2L deficiency.