The SARS-CoV-2 protein ORF3a inhibits fusion of autophagosomes with lysosomes

Zhang, Yabin; Sun, Hao; Pei, Rongjuan; Mao, Binli; Zhao, Zhenyu; Li, Huihui; Lin, Yong; Lu, Kefeng

doi:10.1038/s41421-021-00268-z

Cited by 185 publications

(236 citation statements)

References 71 publications

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“…(Wang et al, 2021). Recent study showed that SARS-CoV-2 ORF3a blocks autophagosome maturation by blocking HOPSmediated SNARE complex assembly (Miao et al, 2021;Zhang et al, 2021), suggesting ORF3a may target multiple protein complexes required for autophagosome-lysosome fusion to facilitate SARS-CoV-2 replication. Given autophagy's role in the innate antiviral immune response to restrict infecting pathogens, it is not surprising that viruses are in a constant arms race to remodel the autophagic membranes for their own benefit during replication (Choi et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Actually, nsp6 homologs from multiple coronaviruses, such as avian coronavirus, mouse hepatitis virus, SARS-CoV, and SARS-CoV-2, affect autophagosome membrane expansion, resulting in small autophagosome (Cottam et al, 2014). Besides nsp6 and ORF3a, ORF7a, and M of SARS-CoV-2 also inhibit autophagy at different levels, while within SARS-CoV-2-encoded proteins, ORF3a shows the most potent capability on autophagy modulation (Miao et al, 2021;Zhang et al, 2021). Manipulation of cellular autophagy pathway is a common signature of coronaviruses and ORF3a is a potential target to limit SARS-CoV-2 replication.…”

Section: Discussionmentioning

confidence: 99%

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ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute Respiratory Syndrome Coronavirus-2 Replication

Wang

Zhu

et al. 2021

Front. Cell Dev. Biol.

104

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the causative agent for the coronavirus disease 2019 (COVID-19) pandemic and there is an urgent need to understand the cellular response to SARS-CoV-2 infection. Beclin 1 is an essential scaffold autophagy protein that forms two distinct subcomplexes with modulators Atg14 and UVRAG, responsible for autophagosome formation and maturation, respectively. In the present study, we found that SARS-CoV-2 infection triggers an incomplete autophagy response, elevated autophagosome formation but impaired autophagosome maturation, and declined autophagy by genetic knockout of essential autophagic genes reduces SARS-CoV-2 replication efficiency. By screening 26 viral proteins of SARS-CoV-2, we demonstrated that expression of ORF3a alone is sufficient to induce incomplete autophagy. Mechanistically, SARS-CoV-2 ORF3a interacts with autophagy regulator UVRAG to facilitate PI3KC3-C1 (Beclin-1-Vps34-Atg14) but selectively inhibit PI3KC3-C2 (Beclin-1-Vps34-UVRAG). Interestingly, although SARS-CoV ORF3a shares 72.7% amino acid identity with the SARS-CoV-2 ORF3a, the former had no effect on cellular autophagy response. Thus, our findings provide the mechanistic evidence of possible takeover of host autophagy machinery by ORF3a to facilitate SARS-CoV-2 replication and raise the possibility of targeting the autophagic pathway for the treatment of COVID-19.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute Respiratory Syndrome Coronavirus-2 Replication

Wang

Zhu

et al. 2021

Front. Cell Dev. Biol.

104

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“…Several recent studies uncovered the detailed mechanism of how SARS-CoV-2 p3a blocks autophagy [26,35,38,39]. Interestingly, autophagy induction by starvation, INK128, and blocks autophagosome turnover by p3a, p7a, and E protein (not shown).…”

Section: Protein 3a Affects Autophagosome/amphisome-lysosome Fusionmentioning

confidence: 98%

“…This block is consistent with SARS-CoV-2 infection in Calu-3 and Caco-2 cells that caused increased levels of both LC3-II and SQSTM1 [35]. Three viral proteins might be responsible for such a block: p3a, p7a, and envelope (E) protein (with p3a being the most prominent), because they were able to cause decreased autophagosome turnover (increased levels of LC3-II and SQSTM1) during ectopic expression in HEK293T, HeLa, and A549 cells [35,38,39]. Interestingly, a couple of SARS-CoV-2 proteins (NSP6 and p3a) can interact with and/or control the levels of select autophagic proteins [26].…”

Section: Proteins 3a 7a and E Block Autophagosome Turnovermentioning

confidence: 99%

The Molecular Interplay between Human Coronaviruses and Autophagy

Shroff

Nazarko

2021

Cells

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Coronavirus disease 2019 (COVID-19), caused by a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has instantaneously emerged as a worldwide pandemic. However, humans encountered other coronaviruses in the past, and they caused a broad range of symptoms, from mild to life-threatening, depending on the virus and immunocompetence of the host. Most human coronaviruses interact with the proteins and/or double-membrane vesicles of autophagy, the membrane trafficking pathway that degrades and recycles the intracellular protein aggregates, organelles, and pathogens, including viruses. However, coronaviruses often neutralize and hijack this pathway to complete their life cycle. In this review, we discuss the interactions of human coronaviruses and autophagy, including recent data from SARS-CoV-2-related studies. Some of these interactions (for example, viral block of the autophagosome–lysosome fusion), while being conserved across multiple coronaviruses, are accomplished via different molecular mechanisms. Therefore, it is important to understand the molecular interplay between human coronaviruses and autophagy for developing efficient therapies against coronaviral diseases.

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“…The SARS-CoV-2 ORF3a protein, which presents 72.4% a.a identity with the SARS-CoV-1 ORF3a protein and 97.8% with the bat-SL-CoV-RaTG13 ORF3a, retains six functional domains (I-VI) (Figure 4A and Supplementary Table 1). These functional domains are linked to virulence, infectivity, ion channel formation and virus release (Issa et al, 2020;Kern et al, 2020) and as the ORF3a protein of SARS-CoV-1, the ORF3a protein SARS-CoV-2 retains the capacity to induce apoptosis (Ren et al, 2020) and also to inhibit fusion autophagosomes with lysosomes (Zhang et al, 2021b).…”

Section: Orf3a and 3b Proteinsmentioning

confidence: 99%

Coronavirus, the King Who Wanted More Than a Crown: From Common to the Highly Pathogenic SARS-CoV-2, Is the Key in the Accessory Genes?

Chazal

2021

Front. Microbiol.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that emerged in late 2019, is the etiologic agent of the current “coronavirus disease 2019” (COVID-19) pandemic, which has serious health implications and a significant global economic impact. Of the seven human coronaviruses, all of which have a zoonotic origin, the pandemic SARS-CoV-2, is the third emerging coronavirus, in the 21st century, highly pathogenic to the human population. Previous human coronavirus outbreaks (SARS-CoV-1 and MERS-CoV) have already provided several valuable information on some of the common molecular and cellular mechanisms of coronavirus infections as well as their origin. However, to meet the new challenge caused by the SARS-CoV-2, a detailed understanding of the biological specificities, as well as knowledge of the origin are crucial to provide information on viral pathogenicity, transmission and epidemiology, and to enable strategies for therapeutic interventions and drug discovery. Therefore, in this review, we summarize the current advances in SARS-CoV-2 knowledges, in light of pre-existing information of other recently emerging coronaviruses. We depict the specificity of the immune response of wild bats and discuss current knowledge of the genetic diversity of bat-hosted coronaviruses that promotes viral genome expansion (accessory gene acquisition). In addition, we describe the basic virology of coronaviruses with a special focus SARS-CoV-2. Finally, we highlight, in detail, the current knowledge of genes and accessory proteins which we postulate to be the major keys to promote virus adaptation to specific hosts (bat and human), to contribute to the suppression of immune responses, as well as to pathogenicity.

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The SARS-CoV-2 protein ORF3a inhibits fusion of autophagosomes with lysosomes

Cited by 185 publications

References 71 publications

ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute Respiratory Syndrome Coronavirus-2 Replication

ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute Respiratory Syndrome Coronavirus-2 Replication

The Molecular Interplay between Human Coronaviruses and Autophagy

Coronavirus, the King Who Wanted More Than a Crown: From Common to the Highly Pathogenic SARS-CoV-2, Is the Key in the Accessory Genes?

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