The interplay between emerging human coronavirus infections and autophagy

Abstract

ABSTRACT Following outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2002 and 2012, respectively, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third highly pathogenic emerging human coronavirus (hCoV). SARS-CoV-2 is currently causing the global coronavirus disease 2019 (COVID-19) pandemic. CoV infections in target cells may stimulate the formation of numerous double-membrane autophagosomes and induce autophagy. Several studies provided evidence that hCoV infections are closely related to various cellular aspects associated with autophagy. Autophagy may even promote hCoV infection and replication. However, so far it is unclear how hCoV infections induce autophagy and whether the autophagic machinery is necessary for viral propagation. Here, we summarize the most recent advances concerning the mutual interplay between the autophagic machinery and the three emerging hCoVs, SARS-CoV, MERS-CoV, and SARS-CoV-2 and the model system mouse hepatitis virus. We also discuss the applicability of approved and well-tolerated drugs targeting autophagy as a potential treatment against COVID-19.

Keywords: Autophagy; MERS-CoV; MHV; SARS-CoV; SARS-CoV-2; coronavirus.

Figure 1.

Replication cycle of coronavirus and autophagy pathways. (1) Schematic diagram showing the general replication cycle of CoV. CoV infection begins with the attachment of spike (S) protein to the cognate cellular receptor, which then promotes the fusion of the viral and cell plasma membrane and induces endocytosis. Subsequently, the nucleocapsid is released to the cytoplasm and the gRNA is translated through the ribosome to produce polyproteins pp1a and pp1ab. These are then cleaved by proteases to generate NSPs, which induce the rearrangement of the cellular membrane to form DMVs, to which the viral RTCs are anchored. The viral gRNA is replicated via a negative-sense intermediate, and sgRNA is synthesized by discontinuous transcription. The sgRNAs encode the viral accessory and structural proteins. Particle assembly occurs in the ERGIC, and smooth-walled vesicles bud out to egress via exocytosis. (2) The autophagy pathway. Under various inducing signals (e.g. amino acid starvation and pathogen infection), autophagy is initiated to form isolation membranes (phagophores) through omegasome intermediates. Closure of the isolation membrane results in formation of the autophagosome, which can fuse with late endosome to form an amphisome. Finally, amphisome and lysosome fusion leads to the degradation of autophagosome contents by lysosomal hydrolases in the autolysosome. CoV, coronavirus; EE, early endosome; ERGIC, ER-Golgi intermediate complex; gRNA, genomic RNA; LE /MVB, late endosome /multivesicular body; NSP, non-structural protein; sgRNA, sub-genomic RNA.

Figure 2.

A proposed model of the interaction of emerging human coronaviruses and autophagy in host cells. Emerging human CoVs (SARS-CoV, MERS-CoV, or SARS-CoV-2) modulate multiple phases of autophagy in infected host cells. (1) At the start of the autophagic process, SARS-CoV and SARS-CoV-2 NSP6 proteins induce the formation of omegasome intermediates. Moreover, all three CoVs can activate the ULK1 complex to promote phagophore formation via the AMPK/MTOR signalling pathway. (2) MERS-CoV and SARS-CoV-2 facilitate AKT1/SKP2-dependent degradation of BECN1 to inhibit vesicle nucleation. Conversely, SARS-CoV and MERS-CoV PLpro deubiquitinates BECN1 to promote autophagy induction. (3) SARS-CoV NSPs and spike (S) proteins cause ER stress, triggering the UPR, and then promote phagophore elongation by activating ATG5-12-16L complex. (4) SARS-CoV and MERS-CoV PLpro induces incomplete autophagy by impairing autophagosome maturation by blocking the fusion of autophagosomes and lysosomes. Additionally, SARS-CoV ORF8b can cause lysosomal damage. UPR, unfolded protein response; ORF, open reading frame; PI3KC3-C1, class III phosphatidylinositol 3-kinase complex I; PLpro, papain protease.