Herpes Simplex Virus type 1 (HSV-1) infects mucosal epithelial cells and establishes life-long infections in sensory neurons. Following reactivation, the virus is transferred anterograde to the initial site of infection or to sites innervated by infected neurons, causing vesicular lesions. Upon immunosuppression frequent HSV-1 reactivation can cause severe diseases such as blindness and encephalitis. Autophagy is a process whereby cell components are recycled, but it also serves as a defense mechanism against pathogens. HSV-1 is known to combat autophagy through the functions of the 134.5 protein, which prevents formation of the autophagophore by binding to Beclin-1, a key factor involved in the elongation of the isolation membrane, and by redirecting the protein phosphatase 1 α (PP1α) to dephosphorylate the translation initiation factor 2α (eIF2α) to prevent host translational shutoff. Other viral proteins that counteract innate immunity negatively impact autophagy. Here, we present a novel strategy of HSV-1 to evade the host, through the down-regulation of the autophagy adaptor protein sequestosome (p62/SQSTM1) and of the mitophagy adaptor optineurin (OPTN). This down-modulation occurs during the early steps of the infection. We also found that the Infected Cell Protein 0 (ICP0) of the virus mediates the down-modulation of the two autophagy adaptors in a mechanism independent of its E3 ubiquitin ligase activity. Cells depleted of either p62 or OPTN could mount greater antiviral responses, whereas cells expressing exogenous p62 displayed decreased virus yields. We conclude that down-regulation of p62/SQSTM1 and OPTN is a viral strategy to counteract the host.
Autophagy is a homeostatic mechanism of cells to recycle components, as well as a defense mechanism to get rid of pathogens. Strategies that HSV-1 has developed to counteract autophagy have been described and involve inhibition of autophagosome formation or indirect mechanisms. Here, we present a novel mechanism that involves down-regulation of two major autophagy adaptor proteins, sequestosome 1 (p62/SQSTM1) and optineurin (OPTN). These findings generate the question: Why does the virus target two major autophagy adaptors if it has mechanisms to block autophagosome formation? P62/SQSTM1 and OPTN proteins have pleiotropic functions, including regulation of innate immunity, inflammation, protein sorting and chromatin remodeling. The decrease in virus yields in the presence of exogenous p62/SQSTM1 suggests that these adaptors have an antiviral function. Thus, HSV-1 could have developed multiple strategies to incapacitate autophagy to ensure replication. Alternatively, the virus could target another antiviral function of these proteins.