SQSTM1 promotes selective autophagic degradation of multiple PRRSV proteins via recruiting E3 ligase TRAF6 to inhibit viral replication
Description
Porcine reproductive and respiratory syndrome (PRRS) is an economically significant disease affecting the global porcine industry, caused by porcine reproductive and respiratory syndrome virus (PRRSV). Although it has been reported that PRRSV can exploit autophagy to facilitate its own replication, the role of selective autophagy during PRRSV replication remains largely unknown. The present study showed that the autophagic cargo receptor SQSTM1 is a newly identified host restrictive factor against PRRSV. Overexpression of SQSTM1 promoted the autophagic degradation of PRRSV Nsp5, Nsp12, GP4, and GP5 proteins. Subsequently, GP4 and GP5 was used as the target proteins to investigate the mechanism underlying the degradation of PRRSV proteins by SQSTM1. Overexpression of SQSTM1 promoted the autophagy adaptor protein LC3 to recruit GP4, as well as its transport to LAMP2-positive lysosomal compartments for subsequent autophagy-lysosomal-mediated degradation. SQSTM1 interacts with both GP4 and GP5 proteins, and promotes the polyubiquitination of GP4 and GP5 by recruiting the host E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6). Further analysis revealed that TRAF6 catalyzes the K63-linked, but not K48-linked polyubiquitination of GP4 at K115 and of GP5 at K59, which are indispensable for their interaction with SQSTM1 and subsequent degradation. Knockdown of TRAF6 abolished SQSTM1-mediated degradation of Nsp5, Nsp12, GP4, and GP5, as well as the anti-PRRSV activity, implying a synergistic effect of SQSTM1 and TRAF6 in degrading PRRSV proteins and suppressing viral replication. The present study is the first to demonstrate that selective autophagy plays an important role in host defense against PRRSV infection, which provides new insights for the development of anti-PRRSV drugs or vaccines.
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Institutions
- Henan Agricultural UniversityHenan, Zhengzhou