ATG16L1 promotes virus trafficking to early endosomes and conducts its degradation by 2BC to benefit foot-and-mouth disease virus replication.

Abstract

The whole life cycle of the highly pathogenic foot-and-mouth disease virus (FMDV) significantly depends on the host determinants to achieve its infection. ATG16L1 is well known to be required to form the autophagosomes membrane at the early steps of autophagy, while its non-autophagic roles in FMDV infection remain unclear. We found that following entry, FMDV O/Fujian/CHA/5/99 trafficked to early endosomes (EEs) and the trans-Golgi network (TGN), bypassing late endosomes (LEs) /lysosome and recycling endosomes (REs). This specific intracellular distribution mirrored the vesicular sorting pathway involving ATG16L1 that had been reported previously. Further analyses showed that ATG16L1 increased the internalization of FMDV and recruited EEs to facilitate the initial phase of FMDV infection. However, ATG16L1 degraded FMDV 2BC protein in the Golgi via its non-autophagic function to inhibit late stages of FMDV infection. To counteract this, membrane-associated 2BC interacted with ATG16L1 and mediated its reduction via the caspase pathway, thereby sustaining FMDV replication. In conclusion, our evidence suggested that ATG16L1 played dual roles in regulating the life cycle of FMDV.