Human Enterovirus 71 Inhibits RIG-I Signaling By Suppressing The Expression Of TRIM25

Enterovirus 71(EV71)is one of the major pathogens causing hand-footmouth disease(HFMD)and can cause multiple neurological complications.The disease occurs frequently in children under the age of 5 and has a high mortality rate.It has been repeatedly popularized on many occasions around the world,causing serious loss of human life and property security.Therefore,the related prevention and prevention of EV71 virus Treatment is particularly important.RIG-I acts as a receptor for double-stranded RNA in the host cell,and it can help the body recognize viral RNA from outside,active the body's immune signal,and enhance the body's anti-virus ability.TRIM25,an important E3 ubiquitin ligase that ubiquitinates RIG-I,can activate RIG-I by ubiquitinating the N-terminal CARD region of RIG-I after RIG-I recognizes the virus,thereby activating downstream signaling pathways and promoting the expression of type I IFN and the secretion of related inflammatory factors help the host to resist virus invasion.It is known that EV71 can be recognized by the RIG-I signaling pathway after infection and that it can replicate and spread itself in the host cell by inhibiting the RIG-I signaling pathway.However,there are few studies on the detailed regulation mechanism of how EV71 acts on RIG-I signaling pathway,so further research is needed.In this study,we found that EV71 3C protein can inhibit the RIG-I-mediated increase of IFN-? levels and can inhibit the protein expression of RIG-I and TRIM25.At the mRNA level,3C protein of EV71 can inhibit the increase of interferonstimulating genes(ISG15,ISG56)and IFN-? levels.In addition,we found that the expression of TRIM25 can promote the stability of RIG-I,reduce the degradation of EV71 3C protein,and thus promote the recovery of IFN-? levels.The single mutants of active site on TRIM25 which plays an important role in the ubiquitination of RIG-I: TRIM25-L69 A and TRIM25-V72 A of TRIM25 and the TRIM25-RING,TRIM25-Bbox,TRIM25-CCD,and TRIM25-SPRY,which were truncated by the four major domains of TRIM25 alone,did not have the same effect.After a single point mutation of the 3C protease active site of EV71,we was found that the degradation of RIG-I and TRIM25 protein by 3C protein was weakened.In addition,we also explored other major pathogens that can cause HFMD,such as enterovirus(EV-D68)and Coxsackie virus(CVB3,CVA6,CVA16),and found that in addition to CVA16,3C Proteins of CVB3,EV-D68 and CVA6 3C proteins also have inhibitory effects on protein expression of RIG-I and TRIM25.In summary,we have discovered a new mechanism of action of major enteroviruses and Coxsackieviruses in infecting host cells.This will lay the foundation for further research on the molecular pathogenesis of the virus treatment of the disease.