ORF3a of SARS-CoV-2 promotes lysosomal exocytosis-mediated viral egress

Chen, Di; Zheng, Qiwen; Sun, Long; Ji, Mingming; Li, Yan; Deng, Hongyu; Zhao, Hong

doi:10.1016/j.devcel.2021.10.006

Cited by 139 publications

(203 citation statements)

References 52 publications

(110 reference statements)

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“…Integrative imaging revealed that SARS-CoV-2 infection triggers Golgi fragmentation (Cortese et al, 2020), but the cause and consequence of Golgi fragmentation remain largely elusive. While it was generally believed that mature viral particles are carried by Golgi-derived vesicles to the plasma membrane and secreted to the extracellular space Machamer, 2015, 2019), which is also supported by recent publications (Eymieux et al, 2021), some other reports indicated that SARS-CoV-2 virus may be released by lysosomal exocytosis (Chen et al, 2021;Ghosh et al, 2020). Thus, the route that mediates SARS-CoV-2 trafficking from the Golgi to the extracellular space is still controversial.…”

Section: Introductionmentioning

confidence: 90%

SARS-CoV-2 remodels the Golgi apparatus to facilitate viral assembly and secretion

Zhang

Kennedy

Xing

et al. 2022

Preprint

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The ongoing COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an enveloped RNA virus. Despite the high economic and life losses caused by SARS-CoV-2, the detailed viral cycle, especially how it assembles and traffics in the secretory pathway, remains largely unknown. Here, we showed that SARS-CoV-2 infection induces global alterations of the host endomembrane system, including dramatic Golgi fragmentation. Disrupting Golgi function with small molecules strongly inhibits viral infection. Furthermore, expression of several SARS-CoV-2 proteins individually is sufficient to trigger Golgi fragmentation. Significantly, SARS-CoV-2 infection down-regulates GRASP55 but up-regulates TGN46 expression, while expression of GRASP55 or knockdown of TGN46 reduces the infection rate of both USA-WA1 and Delta variants of SARS-CoV-2. Our study reveals that SARS-CoV-2 modulates Golgi structure and function via altering GRASP55 and TGN46 expression to facilitate viral trafficking, indicating the Golgi as a novel therapeutic target to block SARS-CoV-2 infection.

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Section: Introductionmentioning

confidence: 90%

SARS-CoV-2 remodels the Golgi apparatus to facilitate viral assembly and secretion

Zhang

Kennedy

Xing

et al. 2022

Preprint

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“…It mediates trafficking of lysosomes to plasma membrane and exocytosis-related SNARE vesicle fusion proteins by facilitating lysosomal targeting of the BORC-ARL8b complex. SARS-CoV-2 ORF3a-mediated lysosomal exocytosis requires activity of the Ca 2+ channel TRPML3, as elevated cytosolic Ca 2+ concentration was observed in ORF3a -expressing cells but not in control cells, and TRPML3 knockdown blocked ORF3a-mediated lysosomal exocytosis ( Chen et al, 2021 ). The connection between ORF3a-mediated ion channel activity and viral release has also been observed in SARS-CoV ( Lu et al, 2006 ; Schwarz et al, 2011 ).…”

Section: Orf3a As a Viroporin And Its Role In Viral Pathogenesis And ...mentioning

confidence: 99%

“…In addition, Emodin inhibits ORF3a-mediated ion channel activity and prevents viral release in hCoV-OC43-infected rhabdomyosarcoma RD cells ( Schwarz et al, 2011 ). However, SARS-CoV ORF3a may promote viral release through a different mechanism than SARS-CoV-2 because it does not go through the lysosomal exocytosis pathway ( Chen et al, 2021 ). Interestingly, mutational analysis of SARS-CoV-2 ORF3a shows that residues S171 and W193 are critical for promoting lysosomal exocytosis ( Figure 3C ).…”

Section: Orf3a As a Viroporin And Its Role In Viral Pathogenesis And ...mentioning

confidence: 99%

“…Interestingly, mutational analysis of SARS-CoV-2 ORF3a shows that residues S171 and W193 are critical for promoting lysosomal exocytosis ( Figure 3C ). When these two residues (S171 and W193) are introduced into SARS-CoV ORF3a, it gains the ability to promote lysosomal exocytosis ( Chen et al, 2021 ). In addition, adding SARS-CoV-2 ORF3a to CoV-MHV-A59 that has no ORF3a significantly increases virus release ( Chen et al, 2021 ).…”

Section: Orf3a As a Viroporin And Its Role In Viral Pathogenesis And ...mentioning

confidence: 99%

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Understanding the Role of SARS-CoV-2 ORF3a in Viral Pathogenesis and COVID-19

et al. 2022

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The ongoing SARS-CoV-2 pandemic has shocked the world due to its persistence, COVID-19-related morbidity and mortality, and the high mutability of the virus. One of the major concerns is the emergence of new viral variants that may increase viral transmission and disease severity. In addition to mutations of spike protein, mutations of viral proteins that affect virulence, such as ORF3a, also must be considered. The purpose of this article is to review the current literature on ORF3a, to summarize the molecular actions of SARS-CoV-2 ORF3a, and its role in viral pathogenesis and COVID-19. ORF3a is a polymorphic, multifunctional viral protein that is specific to SARS-CoV/SARS-CoV-2. It was acquired from β-CoV lineage and likely originated from bats through viral evolution. SARS-CoV-2 ORF3a is a viroporin that interferes with ion channel activities in host plasma and endomembranes. It is likely a virion-associated protein that exerts its effect on the viral life cycle during viral entry through endocytosis, endomembrane-associated viral transcription and replication, and viral release through exocytosis. ORF3a induces cellular innate and pro-inflammatory immune responses that can trigger a cytokine storm, especially under hypoxic conditions, by activating NLRP3 inflammasomes, HMGB1, and HIF-1α to promote the production of pro-inflammatory cytokines and chemokines. ORF3a induces cell death through apoptosis, necrosis, and pyroptosis, which leads to tissue damage that affects the severity of COVID-19. ORF3a continues to evolve along with spike and other viral proteins to adapt in the human cellular environment. How the emerging ORF3a mutations alter the function of SARS-CoV-2 ORF3a and its role in viral pathogenesis and COVID-19 is largely unknown. This review provides an in-depth analysis of ORF3a protein’s structure, origin, evolution, and mutant variants, and how these characteristics affect its functional role in viral pathogenesis and COVID-19.

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“…Lysosomal exocytosis facilitating the clearance of chemotherapeutics accumulated in this organelle is another important component of lysosome-mediated chemotherapy resistance [65]. A recent study has shown that SARS-CoV-2 ORF3a not only inhibits the autophagy flux but also promotes lysosomal exocytosis [66]. This could confer drug resistance to the cancer cells arising in the setting of persistence SARS-CoV-2 ORF3a presence.…”

Section: Implications For Cancer Treatmentmentioning

confidence: 99%

Autophagy: The Potential Link between SARS-CoV-2 and Cancer

Habibzadeh

Dastsooz

Eshraghi

et al. 2021

Cancers

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COVID-19 infection survivors suffer from a constellation of symptoms referred to as post-acute COVID-19 syndrome. However, in the wake of recent evidence highlighting the long-term persistence of SARS-CoV-2 antigens in tissues and emerging information regarding the interaction between SARS-CoV-2 proteins and various components of the host cell macroautophagy/autophagy machinery, the unforeseen long-term consequences of this infection, such as increased risk of malignancies, should be explored. Although SARS-CoV-2 is not considered an oncogenic virus, the possibility of increased risk of cancer among COVID-19 survivors cannot be ruled out. Herein, we provide an overview of the possible mechanisms leading to cancer development, particularly obesity-related cancers (e.g., colorectal cancer), resulting from defects in autophagy and the blockade of the autophagic flux, and also immune escape in COVID-19 survivors. We also highlight the potential long-term implications of COVID-19 infection in the prognosis of patients with cancer and their response to different cancer treatments. Finally, we consider future directions for further investigations on this matter.

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ORF3a of SARS-CoV-2 promotes lysosomal exocytosis-mediated viral egress

Cited by 139 publications

References 52 publications

SARS-CoV-2 remodels the Golgi apparatus to facilitate viral assembly and secretion

SARS-CoV-2 remodels the Golgi apparatus to facilitate viral assembly and secretion

Understanding the Role of SARS-CoV-2 ORF3a in Viral Pathogenesis and COVID-19

Autophagy: The Potential Link between SARS-CoV-2 and Cancer

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