ORF3a mediated-incomplete autophagy facilitates SARS-CoV-2 replication

Qu, Yafei; Wang, Xin; Zhu, Yangyong; Wang, Yuyan; Yang, Xing; Hu, Gaowei; Liu, Chengrong; Li, Jingjiao; Ren, Shanhui; Xiao, Zixuan; Liu, Zhenshan; Wang, Weili; Li, Ping; Zhang, Rong; Liang, Qiming

doi:10.21203/rs.3.rs-100397/v1

Cited by 7 publications

(13 citation statements)

References 39 publications

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“…Careful analysis of LC3-positive DMVs revealed that only the endogenous non-lipidated LC3-I associates with MHV-induced DMVs, and while the LC3 lipidation machinery was dispensable for MHV replication, decreased LC3 impaired MHV replication ( Reggiori et al, 2010 ). Consistent with viral RO assembly being facilitated by autophagosome formation, but not lysosomal targeting and fusion, a recent study reported an incomplete autophagy response to SARS-CoV-2 infection ( Qu et al, 2020 ). Expression of SARS-CoV-2, but not SARS-CoV, ORF3a, was sufficient to trigger incomplete autophagy, where autophagosome formation is increased, but maturation impaired.…”

Section: Dmv Biogenesismentioning

confidence: 78%

Exploiting Connections for Viral Replication

Wong¹,

Edgar

Martello³

et al. 2021

Front. Cell Dev. Biol.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the COVID-19 (coronavirus disease 2019) pandemic, is a positive strand RNA (+RNA) virus. Like other +RNA viruses, SARS-CoV-2 is dependent on host cell metabolic machinery to survive and replicate, remodeling cellular membranes to generate sites of viral replication. Viral RNA-containing double-membrane vesicles (DMVs) are a striking feature of +RNA viral replication and are abundant in SARS-CoV-2–infected cells. Their generation involves rewiring of host lipid metabolism, including lipid biosynthetic pathways. Viruses can also redirect lipids from host cell organelles; lipid exchange at membrane contact sites, where the membranes of adjacent organelles are in close apposition, has been implicated in the replication of several +RNA viruses. Here we review current understanding of DMV biogenesis. With a focus on the exploitation of contact site machinery by +RNA viruses to generate replication organelles, we discuss evidence that similar mechanisms support SARS-CoV-2 replication, protecting its RNA from the host cell immune response.

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Section: Dmv Biogenesismentioning

confidence: 78%

Exploiting Connections for Viral Replication

Wong¹,

Edgar

Martello³

et al. 2021

Front. Cell Dev. Biol.

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“…ORF, open reading frame; PI3KC3-C1, class Ⅲ phosphatidylinositol 3-kinase complex Ⅰ; PLpro, papain protease. [ 51,52]…”

Section: Discussionmentioning

confidence: 99%

“… NCI-H1299 /Vero FM cells AMPK/MTOR and AKT1/SKP2 signalling pathways Inhibit autophagy [ 50 ] SARS-CoV-2 ORF3a HEK293T /HeLa cells HOPS component VPS39 or autophagy regulator UVRAG; Lysosome damage Block autolysosome formation; Impair lysosomal function. [ 51 , 52 ] …”

Section: Coronavirus Infections and Autophagymentioning

confidence: 99%

“…SARS-CoV-2 infection also decreases autophagy-inducing spermidine and facilitates the AKT1/SKP2-dependent degradation of BECN1. Importantly, two recent studies from different laboratories reported that SARS-CoV-2 infection increased autophagosome formation, but impaired autophagosome maturation [ 51 , 52 ]. Subsequently, they further revealed that ORF3a of SARS-CoV-2 alone was sufficient to trigger an incomplete autophagy response by blocking the fusion of autophagosomes and lysosomes.…”

Section: Coronavirus Infections and Autophagymentioning

confidence: 99%

“…Subsequently, they further revealed that ORF3a of SARS-CoV-2 alone was sufficient to trigger an incomplete autophagy response by blocking the fusion of autophagosomes and lysosomes. Qu et al found that SARS-CoV-2 ORF3a directly interacts with the autophagy regulator UVRAG to selectively inhibit the formation of the BECN1-VPS34-UVRAG complex [ 52 ], while Miao et al found that ORF3a directly interacts with the HOPS component VPS39 to block the interaction of HOPS with autophagosomal STX17 as well as destroy lysosomal function [ 51 ]. Interestingly, both of these two studies found that SARS-CoV ORF3a failed to increase autophagosome formation and impair autophagosome maturation, indicating that ORF3a-induced incomplete autophagy is a unique signature of SARS-CoV-2 infection.…”

Section: Coronavirus Infections and Autophagymentioning

confidence: 99%

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The interplay between emerging human coronavirus infections and autophagy

Zhao

Mao

et al. 2021

Emerging Microbes & Infections

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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.

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Drugs that offer the potential to reduce hospitalization and mortality from SARS-CoV-2 infection: The possible role of the sigma-1 receptor and autophagy

Brimson

Prasanth

Malar

et al. 2021

Expert Opinion on Therapeutic Targets

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Introduction: Despite the availability of new vaccines for SARS-CoV-2, there has been slow uptake and problems with supply in some parts of the world. Hence, there is still a necessity for drugs that can prevent hospitalization of patients and reduce the strain on health care systems. Drugs with sigma affinity potentially provide protection against the most severe symptoms of SARS-COV-2 and could prevent mortality via interactions with the sigma-1 receptor. Areas covered: This review examines the role of the sigma-1 receptor and autophagy in SARS-CoV-2 infections and how they may be linked. The authors reveal how sigma ligands may reduce the symptoms, complications, and deaths resulting from SARS-CoV-2 and offer insights on those patient cohorts that may benefit most from these drugs. Expert opinion: Drugs with sigma affinity potentially offer protection against the most severe symptoms of SARS-CoV-2 via interactions with the sigma-1 receptor. Agonists of the sigma-1 receptor may provide protection of the mitochondria, activate mitophagy to remove damaged and leaking mitochondria, prevent ER stress, manage calcium ion transport, and induce autophagy to prevent cell death in response to infection.

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ORF3a mediated-incomplete autophagy facilitates SARS-CoV-2 replication

Cited by 7 publications

References 39 publications

Exploiting Connections for Viral Replication

Exploiting Connections for Viral Replication

The interplay between emerging human coronavirus infections and autophagy

Drugs that offer the potential to reduce hospitalization and mortality from SARS-CoV-2 infection: The possible role of the sigma-1 receptor and autophagy

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