Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease

Area of Science:

• Molecular Biology
• Immunology
• Dermatology

Background:

• Inborn errors of nucleic acid metabolism can trigger autoimmune and autoinflammatory diseases via aberrant nucleic acid sensing.
• The SKIV2L RNA exosome machinery was believed crucial for preventing self-RNA-induced interferon responses.

Purpose of the Study:

• To elucidate the physiological role of SKIV2L in mammalian skin and T cell homeostasis.
• To investigate the molecular mechanisms underlying SKIV2L deficiency-related autoinflammatory conditions.

Main Methods:

• Utilized Skiv2l-deficient mouse models with epidermis-specific gene deletion.
• Analyzed epidermal and T cell homeostasis, skin inflammation, and hair abnormalities.
• Investigated the involvement of the mTORC1 pathway and treated mice with rapamycin.

Main Results:

• Skiv2l deficiency disrupted epidermal and T cell homeostasis independently of interferon signaling.
• Mice exhibited skin inflammation, hair abnormalities, keratinocyte hyperproliferation, and impaired skin barrier.
• Skiv2l-deficient T cells were hyperactivated and attacked skin and hair follicles.
• SKIV2L loss activated the mTORC1 pathway in keratinocytes and T cells.
• Rapamycin treatment ameliorated skin hyperplasia and inflammation in deficient mice.

Conclusions:

• SKIV2L plays a critical role in maintaining mammalian skin and T cell homeostasis.
• Cytoplasmic RNA quality control failure, sensed by mTORC1, drives autoinflammatory disease.
• SKIV2L-associated trichohepatoenteric syndrome (THES) is proposed as a novel mTORopathy potentially treatable with sirolimus.