Friend or Foe? Implication of the autophagy-lysosome pathway in SARS-CoV-2 infection and COVID-19

Wang, He; Gao, Yuan; Zhou, Jing; Shi, Yi; Xia, Dajing; Shen, Han‐Ming

doi:10.7150/ijbs.72544

Cited by 18 publications

(11 citation statements)

References 154 publications

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“…The autophagy machinery has been linked with viral replication and egression in multiple works, but very little is known about the interplay between this pathway and SARS‐CoV‐2 entry (He et al , 2022; Lan et al , 2022). However, there are evidences supporting that lysosomotropic agents that disrupt the autophagy‐lysosome pathway, such as azithromycin or chloroquine/hydroxychloroquine, are promising drugs to block SARS‐CoV‐2 entry (Norinder et al , 2020; Du et al , 2021; Ou et al , 2021; Yuan et al , 2022).…”

Section: Discussionmentioning

confidence: 99%

Autophagy‐linked plasma and lysosomal membrane protein PLAC8 is a key host factor for SARS‐CoV‐2 entry into human cells

et al. 2022

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Better understanding on interactions between SARS-CoV-2 and host cells should help to identify host factors that may be targetable to combat infection and COVID-19 pathology. To this end, we have conducted a genome-wide CRISPR/Cas9-based loss-offunction screen in human lung cancer cells infected with SARS-CoV-2-pseudotyped lentiviruses. Our results recapitulate many findings from previous screens that used full SARS-CoV-2 viruses, but also unveil two novel critical host factors: the lysosomal efflux transporter SPNS1 and the plasma and lysosomal membrane protein PLAC8. Functional experiments with full SARS-CoV-2 viruses confirm that loss-of-function of these genes impairs viral entry. We find that PLAC8 is a key limiting host factor, whose overexpression boosts viral infection in eight different human lung cancer cell lines. Using single-cell RNA-Seq data analyses, we demonstrate that PLAC8 is highly expressed in ciliated and secretory cells of the respiratory tract, as well as in gut enterocytes, cell types that are highly susceptible to SARS-CoV-2 infection. Proteomics and cell biology studies suggest that PLAC8 and SPNS1 regulate the autophagolysosomal compartment and affect the intracellular fate of endocytosed virions.

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Section: Discussionmentioning

confidence: 99%

Autophagy‐linked plasma and lysosomal membrane protein PLAC8 is a key host factor for SARS‐CoV‐2 entry into human cells

et al. 2022

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“…Therefore, N protein may promote or repress SARS-CoV-2 replication by downregulating or upregulating IFN expression, respectively. Finally, we observed that N protein can induce autophagy, which reportedly promotes or inhibits SARS-CoV-2 replication 50 . Therefore, N protein may regulate SARS-CoV-2 replication in an autophagy-dependent manner.…”

Section: Discussionmentioning

confidence: 76%

SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia

Luo,

Zhou,

et al. 2023

Preprint

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Age is a major risk factor for coronavirus disease (COVID-19)-associated severe pneumonia and mortality; however, the underlying mechanism remains unclear. Herein, we investigated whether age-related deregulation of RNAi components and RNA splicing factors affects COVID-19 severity. Decreased expression of RNAi components (Dicer and XPO5) and splicing factors (SRSF3 and hnRNPA3) correlated with increased severity of COVID-19 and SARS-CoV-2 nucleocapsid (N) protein-induced pneumonia. N protein induced autophagic degradation of Dicer, XPO5, SRSF3, and hnRNPA3, repressing miRNA biogenesis and RNA splicing and inducing DNA damage, proteotoxic stress, and pneumonia. Dicer, XPO5, SRSF3, and hnRNPA3 were downregulated with age in mouse lung tissues. Older mice experienced more severe N protein-induced pneumonia than younger mice. However, treatment with a poly(ADP-ribose) polymerase inhibitor (PJ34) or aromatase inhibitor (anastrozole) relieved N protein-induced pneumonia by restoring Dicer, XPO5, SRSF3, and hnRNPA3 expression. These findings will aid in developing improved treatments for SARS-CoV-2-associated pneumonia.

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“…Autophagy activation has also been put forward as a therapeutic strategy to inhibit NLRP3 inflammasome-mediated lung inflammation in COVID-19 [66]. However, the clinical benefit of autophagyrelated therapy or drugs remains to be demonstrated [64,66,67].…”

Section: Key Pointsmentioning

confidence: 99%

“…Thus, autophagy manipulation emerged as an interesting target to reduce viral load and combat SARS-CoV-2 infection [64,65]. Autophagy activation has also been put forward as a therapeutic strategy to inhibit NLRP3 inflammasome-mediated lung inflammation in COVID-19 [66]. However, the clinical benefit of autophagyrelated therapy or drugs remains to be demonstrated [64,66,67].…”

Section: Key Pointsmentioning

confidence: 99%

Nutrition and autophagy deficiency in critical illness

Vanhorebeek

Casaer

Gunst

2023

Current Opinion in Critical Care

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Purpose of review Critical illness imposes a severe insult on the body, with various stressors triggering pronounced cell damage. This compromises cellular function, leading to a high risk of multiple organ failure. Autophagy can remove damaged molecules and organelles but appears insufficiently activated during critical illness. This review discusses insight into the role of autophagy in critical illness and the involvement of artificial feeding in insufficient autophagy activation in critical illness. Recent findings Animal studies manipulating autophagy have shown its protective effects against kidney, lung, liver, and intestinal injury after several critical insults. Autophagy activation also protected peripheral, respiratory, and cardiac muscle function, despite aggravated muscle atrophy. Its role in acute brain injury is more equivocal. Animal and patient studies showed that artificial feeding suppressed autophagy activation in critical illness, particularly with high protein/amino acid doses. Feeding-suppressed autophagy may explain short and long-term harm by early enhanced calorie/protein feeding in large randomized controlled trials. Summary Insufficient autophagy during critical illness is at least partly explained by feeding-induced suppression. This may explain why early enhanced nutrition failed to benefit critically ill patients or even induced harm. Safe, specific activation of autophagy avoiding prolonged starvation opens perspectives for improving outcomes of critical illness.

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Friend or Foe? Implication of the autophagy-lysosome pathway in SARS-CoV-2 infection and COVID-19

Cited by 18 publications

References 154 publications

Autophagy‐linked plasma and lysosomal membrane protein PLAC8 is a key host factor for SARS‐CoV‐2 entry into human cells

Autophagy‐linked plasma and lysosomal membrane protein PLAC8 is a key host factor for SARS‐CoV‐2 entry into human cells

SARS-CoV-2 N protein-induced Dicer, XPO5, SRSF3, and hnRNPA3 downregulation causes pneumonia

Nutrition and autophagy deficiency in critical illness

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