Autophagic degradation of CD81 by hepatitis C virus: a novel mechanism underlying viral superinfection exclusion (740.1)

Abstract

Autophagy, a lysosomal degradation pathway, is known to positively regulate HCV replication. However, it remains unknown how cells withstand HCV productive replication in the cell context of autophagy activation. Here we showed that HCV infection triggered superinfection exclusion through downregulating the cell surface and total expressions of CD81, an important HCV entry (co)receptor. HCV‐induced downregulation of CD81 was associated with the autophagy‐mediated, lysosomal degradation process as interference with autophagolysosome maturation with pharmacological inhibitors restored the level of CD81 in HCV‐infected cells. Moreover, confocal and electron microscopy analyses showed that HCV infection led to engulfment of CD81 within autophagic vacuoles matured at different stages of autophagy, and that these CD81‐coresiding autophagosomes were originated from endoplasmic reticulum (ER)‐derived preautophagosomal structure (PAS). Knockdown of autophagy‐related genes required for the assembly of PAS in HCV‐infected cells relieved cytoplasmic retention of CD81, restored CD81 surface expression, and re‐conferred cell permissiveness to HCV infection. Our findings reveal a novel role of autophagy in restricting HCV superinfection by sequestration and degradation of its entry (co)receptor through ER‐originated PAS and fusion with lysosome, thereby maintaining virus‐cell homeostasis.