VISA (also known as MAVS, IPS-1 and Cardif) is an essential adaptor protein in innate immune response to RNA virus. The protein level of VISA is delicately regulated before and after viral infection to ensure the optimal activation and timely termination of innate antiviral response. It has been reported that several E3 ubiquitin ligases can mediate the degradation of VISA, but how the stability of VISA is maintained before and after viral infection remains enigmatic. In this study, we found that the ER-associated inactive rhomboid protein 2 (iRhom2) plays an essential role in mounting an efficient innate immune response to RNA virus by maintaining the stability of VISA through distinct mechanisms. In un-infected and early infected cells, iRhom2 mediates auto-ubiquitination and degradation of the E3 ubiquitin ligase RNF5 and impairs the assembly of VISA-RNF5-GP78 complexes, thereby antagonizes ER-associated degradation (ERAD) of VISA. In the late phase of viral infection, iRhom2 mediates proteasome-dependent degradation of the E3 ubiquitin ligase MARCH5 and impairs mitochondria-associated degradation (MAD) of VISA. Maintenance of VISA stability by iRhom2 ensures efficient innate antiviral response at the early phase of viral infection and ready for next round of response. Our findings suggest that iRhom2 acts as a checkpoint for the ERAD/MAD of VISA, which ensures proper innate immune response to RNA virus.

VISA（也称为MAVS，IPS-1和Cardif）是对RNA病毒的先天免疫应答中必不可少的衔接蛋白。在病毒感染之前和之后，VISA的蛋白质水平受到精细调节，以确保最佳激活并及时终止先天性抗病毒反应。据报道，几种E3泛素连接酶可以介导VISA的降解，但是如何维持VISA在病毒感染之前和之后的稳定性仍然是个谜。在这项研究中，我们发现与ER相关的非活性菱形蛋白2（iRhom2）在通过不同的机制维持VISA的稳定性而对RNA病毒进行有效的先天免疫应答中起着至关重要的作用。在未感染和早期感染的细胞中，iRhom2介导E3泛素连接酶RNF5的自身泛素化和降解，并损害VISA-RNF5-GP78复合物的装配，从而拮抗VIS的ER相关降解（ERAD）。在病毒感染的晚期，iRhom2介导蛋白酶体依赖性的E3泛素连接酶MARCH5降解，并削弱VISA的线粒体相关降解（MAD）。通过iRhom2维持VISA稳定性可确​​保在病毒感染的早期有效进行先天抗病毒反应，并为下一轮反应做好准备。我们的发现表明，iRhom2可以作为VISA的ERAD / MAD的检查点，以确保对RNA病毒具有适当的先天免疫应答。iRhom2介导蛋白酶体依赖的E3泛素连接酶MARCH5的降解，并削弱了VISA的线粒体相关降解（MAD）。通过iRhom2维持VISA稳定性可确​​保在病毒感染的早期有效进行先天抗病毒反应，并为下一轮反应做好准备。我们的发现表明，iRhom2可以作为VISA的ERAD / MAD的检查点，以确保对RNA病毒具有适当的先天免疫应答。iRhom2介导蛋白酶体依赖的E3泛素连接酶MARCH5的降解，并削弱了VISA的线粒体相关降解（MAD）。通过iRhom2维持VISA稳定性可确​​保在病毒感染的早期有效进行先天抗病毒反应，并为下一轮反应做好准备。我们的发现表明，iRhom2可以作为VISA的ERAD / MAD的检查点，以确保对RNA病毒具有适当的先天免疫应答。