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Review
. 2020 Jul 5;9(7):1619.
doi: 10.3390/cells9071619.

Canonical and Noncanonical Autophagy as Potential Targets for COVID-19

Melissa Bello-Perez  1 , Isabel Sola  1 , Beatriz Novoa  2 , Daniel J Klionsky  3 , Alberto Falco  4
Affiliations
Review

Canonical and Noncanonical Autophagy as Potential Targets for COVID-19

Melissa Bello-Perez et al. Cells. .

Abstract

The SARS-CoV-2 pandemic necessitates a review of the molecular mechanisms underlying cellular infection by coronaviruses, in order to identify potential therapeutic targets against the associated new disease (COVID-19). Previous studies on its counterparts prove a complex and concomitant interaction between coronaviruses and autophagy. The precise manipulation of this pathway allows these viruses to exploit the autophagy molecular machinery while avoiding its protective apoptotic drift and cellular innate immune responses. In turn, the maneuverability margins of such hijacking appear to be so narrow that the modulation of the autophagy, regardless of whether using inducers or inhibitors (many of which are FDA-approved for the treatment of other diseases), is usually detrimental to viral replication, including SARS-CoV-2. Recent discoveries indicate that these interactions stretch into the still poorly explored noncanonical autophagy pathway, which might play a substantial role in coronavirus replication. Still, some potential therapeutic targets within this pathway, such as RAB9 and its interacting proteins, look promising considering current knowledge. Thus, the combinatory treatment of COVID-19 with drugs affecting both canonical and noncanonical autophagy pathways may be a turning point in the fight against this and other viral infections, which may also imply beneficial prospects of long-term protection.

Keywords: COVID-19; SARS-CoV-2; antiviral; autophagy; canonical autophagy; coronavirus; noncanonical autophagy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Diagram of the autophagy pathway including the convergence of the endocytic pathway. Autophagy is regulated by three protein complexes: ULK1, comprising of ULK1, ATG13, RB1CC1/FIP200 and ATG101; class III PtdIns3K, comprising of ATG14, BECN1, PIK3R4/VPS15 and PIK3C3/VPS34 and ATG16L1, comprising of ATG16L1, ATG5 and ATG12. Under starvation conditions, MTOR is inactivated allowing ULK1 complex formation, and activation of the PtdIns3K, which creates the PtdIns3P-rich regions on the surface of the omegasome. WIPI proteins recognize these domains and recruit the ATG16L1 complex, which facilitates lipidation of LC3-I to form LC3-II. Receptors such as SQSTM1/p62 bind to ubiquitinated cargo and LC3-II to facilitate selective autophagy. Cytoplasmic cargo includes damaged mitochondria, organelles, proteins, nucleic acids, intracellular bacteria, etc. Expansion of the phagophore through membrane addition sequesters a portion of the cytoplasm and upon closure forms the autophagosome. These autophagosomes are decorated with RAB7, which leads to the fusion with lysosomes to form the autolysosomes, where the cargo is degraded. The endocytic pathway (used by some viruses) and autophagy converge, resulting in the formation of an amphisome, which also fuses with lysosomes to form autolysosomes. The pink color indicates acidic compartments. Abbreviations: AMPK, AMP activated protein kinase; BCL2, BCL2 apoptosis regulator; BECN1, beclin 1; LAMP2, lysosomal associated membrane protein 2; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MTOR, mechanistic target of rapamycin kinase; PE, phosphoethanolamine; PIK3C3/VPS34, phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15, phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K, phosphatidylinositol 3-kinase; Ptdins3P, phosphatidylinositol-3-phosphate; PTK2/FAK, protein tyrosine kinase 2; RAB7, RAB7, member RAS oncogene family; RB1CC1/FIP200, RB inducible coiled-coil 1; SQSTM1/p62, sequestosome 1; ULK1, unc-51 like autophagy activating kinase 1; WIPI1/2, WD repeat domain, phosphoinositide interacting 1/2; ZFYVE1/DFCP1, zinc finger FYVE-type containing 1.
Figure 2
Figure 2
Diagram of the ER stress unfolded protein response (UPR) pathways triggering autophagy. ER stress can activate autophagy through three different UPR branches: EIF2AK3/PERK, ERN/IRE1 and/or the ATF6 signaling pathway. EIF2AK3/PERK induces autophagy by activating the ATG16L1 complex through ATF4 or by inducing DDIT3/CHOP expression, which indirectly causes BECN1 dissociation from BCL2. ERN/IRE1, through MAPK/JNK, mediates the phosphorylation of BCL2, which causes its dissociation from BECN1. The XBP1 branch enhances the formation of LC3-II. The ATF6 pathway also induces autophagy by inhibiting phosphorylation at the AKT-MTOR pathway. Abbreviations: AKT/PKB, AKT serine-threonine kinase; ATF4/6, activating transcription factor 4/6; DDIT3/CHOP/GADD153, DNA damage inducible transcript 3; EIF2AK3/PERK, eukaryotic translation initiation factor 2 alpha kinase 3; ERN/IRE1, endoplasmic reticulum to nucleus signaling 1; MAPK/JNK, mitogen-activated protein kinase and XBP1, X-box binding protein 1.
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