Coronavirus interactions with the cellular autophagy machinery

Abstract

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is the most recent example of an emergent coronavirus that poses a significant threat to human health. Virus-host interactions play a major role in the viral life cycle and disease pathogenesis, and cellular pathways such as macroautophagy/autophagy prove to be either detrimental or beneficial to viral replication and maturation. Here, we describe the literature over the past twenty years describing autophagy-coronavirus interactions. There is evidence that many coronaviruses induce autophagy, although some of these viruses halt the progression of the pathway prior to autophagic degradation. In contrast, other coronaviruses usurp components of the autophagy pathway in a non-canonical fashion. Cataloging these virus-host interactions is crucial for understanding disease pathogenesis, especially with the global challenge of SARS-CoV-2 and COVID-19. With the recognition of autophagy inhibitors, including the controversial drug chloroquine, as possible treatments for COVID-19, understanding how autophagy affects the virus will be critical going forward. Abbreviations: 3-MA: 3-methyladenine (autophagy inhibitor); AKT/protein kinase B: AKT serine/threonine kinase; ATG: autophagy related; ATPase: adenosine triphosphatase; BMM: bone marrow macrophage; CGAS: cyclic GMP-AMP synthase; CHO: Chinese hamster ovary/cell line; CoV: coronaviruses; COVID-19: Coronavirus disease 2019; DMV: double-membrane vesicle; EAV: equine arteritis virus; EDEM1: ER degradation enhancing alpha-mannosidase like protein 1; ER: endoplasmic reticulum; ERAD: ER-associated degradation; GFP: green fluorescent protein; HCoV: human coronavirus; HIV: human immunodeficiency virus; HSV: herpes simplex virus; IBV: infectious bronchitis virus; IFN: interferon; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCoV: mouse coronavirus; MERS-CoV: Middle East respiratory syndrome coronavirus; MHV: mouse hepatitis virus; NBR1: NBR1 autophagy cargo receptor; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2 (autophagy receptor that directs cargo to phagophores); nsp: non-structural protein; OS9: OS9 endoplasmic reticulum lectin; PEDV: porcine epidemic diarrhea virus; PtdIns3K: class III phosphatidylinositol 3-kinase; PLP: papain-like protease; pMEF: primary mouse embryonic fibroblasts; SARS-CoV: severe acute respiratory syndrome coronavirus; SKP2: S-phase kinase associated protein 2; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; ULK1: unc-51 like autophagy activating kinase 1; Vps: vacuolar protein sorting.

Keywords: Autophagy; COVID-19; ERAD; MERS; SARS-CoV-2; coronavirus.

Figure 1.

Coronavirus interference in the autophagic pathway. Upon induction of the canonical autophagy pathway, ER membranes rearrange to form membranous structures known as omegasomes. These omegasomes then self-fuse into double-membrane vesicles (DMVs), which are termed autophagosomes. Infection by MHV, nsp6 of IBV, and nsp3 of CoV-NL63 promote the formation of these autophagosomes, and viral replication complexes often associate with these structures. However, coronavirus proteins may induce the formation of DMVs directly from the ER independent of the canonical autophagosome machinery, as seen for SARS-CoV nsp3, 4, and 6, EAV nsp2 and 3, and MERS-CoV nsp3 and 4 (see text.) MHV infection induces ER-derived DMVs independent of the autophagic pathway through hijacking of the host cell ERAD machinery. As the autophagic pathway progresses, the autophagosome fuses with the late endosome, then the lysosome, which results in degradation of the autophagosomal cargo. Nascent RNA of MHV colocalizes with late endosomal markers, suggesting that MHV may allow or promote the fusion of the autophagosome with the late endosome. In other cases, coronaviruses inhibit fusion of the autophagosome with the lysosome. One mechanism of blocking fusion is through direct or indirect inhibition of BECN1, a host protein known to promote this fusion. Specifically, the PLP-domain of nsp3 of CoV-NL63 binds BECN1 and STING1, which prevents BECN1 from promoting autophagosome and lysosome fusion and inhibits production of interferon. MERS-CoV inhibits BECN1-mediated fusion through a separate mechanism, by activation of SKP2, which promotes degradation of BECN1. All of these pathways converge in the late endosome or lysosome, although some coronaviruses inhibit fusion with these compartments