The C-Terminal Effector Domain of Non-Structural Protein 1 of Influenza A Virus Blocks IFN-ß Production by Targeting TNF Receptor-Associated Factor 3

Qian, Wei; Wei, Xiaoqin; Guo, Kelei; Li, Yongtao; Lin, Xian; Zou, Zhong; Zhou, Hongbo; Jin, Meilin

Ubiquitination has emerged as a key posttranslational modification that controls induction and shutdown of the interferon response. TRAF3, serving as a crucial functional link, is modified with a polyubiquitin chain providing a scaffold for complex formation, and, not surprisingly, many viruses encode proteins that inhibit ubiquitination processes to overcome host innate responses. Previous studies showed that nairoviruses and arteriviruses encode for ovarian tumor domain-containing proteases that hydrolyze ubiquitin chains from host proteins (50, 51) . In this report, we have shown that NS1/126-225 suppresses the K63linked ubiquitination of TRAF3. It is likely that NS1/126-225 works through recruiting a deubiquitinase to cleave the TRAF3 ubiquitin chain since it has been shown that NS1/126-225 does not belong to any known deubiquitinase family. For example, DUBA, a member of the Otubain (OTUB) family, has been shown to deubiquitinate TRAF3 and negatively regulate TLR3-and RIG-I/ MDA5-mediated IFN induction (52) . It was also shown that two OTUB deubiquitinating enzyme family members, OTUB1 and OTUB2, can deubiquitinate TRAF3 and TRAF6, leading to the inhibition of virus-induced IFN-β expression and cellular antiviral responses (53) . Therefore, whether these proteins, or other DUB proteins, are involved in this regulation, and the detailed regulatory mechanism of TRAF3 activity triggered by NS1/126-225 remains to be discovered.