The interplay of reovirus with autophagy

Abstract

Autophagy participates in multiple fundamental physiological processes, including survival, differentiation, development, and cellular homeostasis. It eliminates cytoplasmic protein aggregates and damaged organelles by triggering a series of events: sequestering the protein substrates into double-membrane vesicles, fusing the vesicles with lysosomes, and then degrading the autophagic contents. This degradation pathway is also involved in various disorders, for instance, cancers and infectious diseases. This paper provides an overview of modulation of autophagy in the course of reovirus infection and also the interplay of autophagy and reovirus.

Figure 1

Regulation of autophagy by ARV. The autophagy process contains several distinct steps, including membrane isolation, nucleation, vesicle formation, fusion of autophagosome with lysosome, and degradation of the cargo followed by release of the degradation products back into the cytosol. The activity of autophagy is regulated by several cellular signaling pathways; mTOR-dependent pathway (via mTORC1), and mTOR-independent pathways (such as TFEB-mediated pathway and cyclical Ca²⁺-calpain-Gαs and cAMP-Epac-PLC-ε-IP3 pathways). Starvation inhibits mTORC1, a downregulator of autophagy, and also induces dephosphorylation of TFEB resulting in the activation of autophagy [2]. Infection of ARV promotes autophagy via the action of p17 protein at the various steps of PI3K-Akt-mTORC1 pathway and also on activation of PKR/eIF2α signaling [9]. In the case of Beclin-1 regulation, Wirawan et al. demonstrated that caspase activation in cells undergoing autophagy has been demonstrated to cleave Beclin-1, thereby inducing apoptosis [10]. The antiapoptotic protein, Bcl-2, interacts with Beclin-1 and inhibits Beclin 1-dependent autophagy [11]. Autophagy and apoptosis are basic cellular pathways that are regulated by JNK-mediated Bcl-2 phosphorylation [12]. JNK1-mediated Bcl-2 phosphorylation interferes with its binding to Beclin-1, thereby promoting autophagy induction [12]. More recently, a report by Wang et al. demonstrated that Akt-mediated phosphorylation of Beclin-1 increased its interactions with 14-3-3 and vimentin, leading to autophagy inhibition [13].