期刊
NATURE IMMUNOLOGY
卷 17, 期 9, 页码 1057-1066出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3510
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资金
- Ministry of Science and Technology of China [2014CB910103, 2012CB910201]
- National Natural Science Foundation of China [31521091, 91429304]
STING is a central adaptor in the innate immune response to DNA viruses. However, the manner in which STING activity is regulated remains unclear. We identified iRhom2 (Inactive rhomboid protein 2') as a positive regulator of DNA-virus-triggered induction of type I interferons. iRhom2 deficiency markedly impaired DNA-virus- and intracellular-DNA-induced signaling in cells, and iRhom2-deficient mice were more susceptible to lethal herpes simplex virus type 1 (HSV-1) infection. iRhom2 was constitutively associated with STING and acted in two distinct processes to regulate STING activity. iRhom2 recruited the translocon-associated protein TRAP beta to the STING complex to facilitate trafficking of STING from the endoplasmic reticulum to perinuclear microsomes. iRhom2 also recruited the deubiquitination enzyme EIF3S5 to maintain the stability of STING through removal of its K48-linked polyubiquitin chains. These results suggest that iRhom2 is essential for STING activity, as it regulates TRAP beta-mediated translocation and EIF3S5-mediated deubiquitination of STING.
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