Role of autophagy in Zika virus infection and pathogenesis

Abstract

Autophagy is an evolutionarily conserved cellular pathway that culminates in lysosomal degradation of selected substrates. Autophagy can serve dual roles in virus infection with either pro- or antiviral functions depending on the virus and the stage of the viral replication cycle. Recent studies have suggested a role for autophagy in Zika virus (ZIKV) replication by demonstrating the accumulation of autophagic vesicles following ZIKV infection in both in vitro and in vivo models. In human fetal neural stem cells, ZIKV inhibits Akt-mTOR signaling to induce autophagy, increase virus replication and impede neurogenesis. However, autophagy also has the potential to limit ZIKV replication, with separate studies demonstrating antiviral roles for autophagy at the maternal-placental-fetal interface, and more specifically, at the endoplasmic reticulum where virus replication is established in an infected cell. Interestingly, ZIKV (and related flaviviruses) has evolved specific mechanisms to overcome autophagy at the ER, thus demonstrating important roles for these autophagic pathways in virus replication and host response. This review summarizes the known roles of autophagy in ZIKV replication and how they might influence virus tissue tropism and disease.

Keywords: Autophagy; Er-phagy; FAM134B; Replication; Zika virus.

Figure 1. Autophagy pathway

Autophagy is initiated through inhibition of mTORC1 signaling. This results in the recruitment and coordinated function of induction and nucleation factors (DFCP1, ATG9, ULK1/2, FIP200 Beclin1, VPS34, ATG14L, classIIIPI3K complex, ATG5, ATG12 and ATG16) at the phagophore assembly site (PAS) that assembles at the MAM (mitochondrial associated membrane). Induction and nucleation is followed by the conjugation of phosphatidylethanolamine (PE) onto LC3-I through a reaction involving the ATG12-ATG5-ATG16 complex to form LC3-II bound onto the autophagosome membrane. LC3-II directly interacts with selective autophagy receptors via their LC3-interacting region [18] to specifically sequester cargo for autophagic degradation. Upon selection of cargo and closure of the nascent autophagosomal membrane, mature autophagosomes fuse with lysosomes utilizing a SNARE protein, syntaxin 17 (STX17), to form the autolysosome which facilitates degradation of cargo.

Figure 2. Autophagy and flavivirus infection

ZIKV engages exposed surface receptors on the host cell and virions are internalized via receptor-dependent endocytosis. The acidic pH of in the endosomal compartments initiates structural changes of the envelope glycoproteins, triggering the fusion of viral and endosomal membranes and release of viral RNA (vRNA) into the cytoplasm. The vRNA is translated into a polyprotein, which is co- and post-translationally processed by viral and host proteases into structural (S) and nonstructural proteins (NS). Of the NS proteins, NS4A, NS4B and NS2B/3 have important roles in manipulating the autophagy pathway. Early in infection, NS4A and NS4B induce membrane curvature and induce autophagy, to mobilize membranes and lipids required for biogenesis of the viral replication complex (induction). The endoplasmic reticulum (ER) is the critical membrane platform on which virus replication is established. Viral manipulation of the ER must induce ER-Phagy, which is actively antagonized (subversion) by the cleavage of the ER-Phagy receptor FAM134B by flavivirusprotease (NS2B/3) (inset). Furthermore, the closely related flavivirus, DENV-2, can block autolysosome formation by preventing fusion of autophagosomes with lysosomes.