iRhom2isessentialforinnateimmunitytoRNAvirusbyantagonizingER- andmitochondria-associateddegradationofVISA.

VISA(also known as MAVS, IPS-1 and Cardif) is anessentialadaptor protein ininnateimmune response toRNAvirus. The protein level ofVISAis delicately regulated before and after viral infection to ensure the optimal activation and timely termination ofinnateantiviral response. It has been reported that several E3 ubiquitin ligases can mediate thedegradationofVISA, but how the stability ofVISAis maintained before and after viral infection remains enigmatic. In this study, we found that theER-associated inactive rhomboid protein 2 (iRhom2) plays anessentialrole in mounting an efficientinnateimmune response toRNAvirusby maintaining the stability ofVISAthrough distinct mechanisms. In un-infected and early infected cells,iRhom2mediates auto-ubiquitination anddegradationof the E3 ubiquitin ligase RNF5 and impairs the assembly ofVISA-RNF5-GP78 complexes, thereby antagonizesER-associateddegradation(ERAD) ofVISA. In the late phase of viral infection,iRhom2mediates proteasome-dependentdegradationof the E3 ubiquitin ligase MARCH5 and impairsmitochondria-associateddegradation(MAD) ofVISA. Maintenance ofVISAstability byiRhom2ensures efficientinnateantiviral response at the early phase of viral infection and ready for next round of response. Our findings suggest thatiRhom2acts as a checkpoint for the ERAD/MAD ofVISA, which ensures properinnateimmune response toRNAvirus.