Viral and Cellular Determinants of Picornavirus-mediated Autophagy Induction
AdvisorJackson, William T
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AbstractMacro-autophagy is a basal cellular process that involves the degradation and turnover of cytosolic components, including elimination of damaged organelles and cytosolic cargo. In response to cell stressors, such as but not limited to, starvation and infection from xenobiotics, autophagy is upregulated. The process is controlled by the upstream autophagy signaling ULK complex, composed of the kinases ULK1 or ULK2, and the scaffold proteins ATG13, RB1CC1, and ATG101. This complex serves as a nexus for signaling pathways from nutrient sensitive kinase complexes such as MTORC1 or AMPK. Poliovirus (PV) has been shown to induce autophagy in infected cells, but the mechanism of initiation has not been completely elucidated. Furthermore, the host cellular factors that are involved in this virus-induced autophagy are unknown. We recently have shown that PV does not require the ULK1/2 complex for replication or autophagic signal induction during infection, demonstrating a novel ULK1/2-independent autophagic signaling pathway. We show that knockdown of RB1CC1, a vital scaffold protein for the ULK1/2 complexes, has no effect on PV replication and does not impede the ability of the virus to induce autophagic signals. Furthermore, PV mediates the elimination of this complex during infection in a mechanism that is not dependent on the proteasome. PV causes the cleavage of an autophagic cargo receptor SQSTM1, which was previously described in CV-B3, and therefore impairs our ability to measure bona fide autophagy during infection. We have also found that several members of the Enterovirus genus: Enterovirus D68 (EV-D68), Coxsackievirus B3 (CV-B3), and Rhinovirus A1 (RV-A1) also do not require the ULK complex for replication or with their respective effects on autophagy. We have evidence that suggests that the BECN1 complex, downstream of the ULK complex, is dispensable for PV. Exogenous expression of viral proteins 2BC and 3A from PV and CV-B3 increase the presence of LC3+ puncta but show no acidification of autophagosomes, suggesting the presence of a secondary acidification signal. We discuss the implications of these findings in regards to the ability of picornaviruses to reformat the induction process for their own benefit.
Molecular Microbiology and Immunology
University of Maryland, Baltimore