Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation

Tabata, Keisuke; Bartenschlager, Ralf; Paul, David; Lee, Ji-Young; Pham, Minh-Tu; Twu, Woan-Ing; Neufeldt, Christopher J.; Cortese, Mirko; Cerikan, Berati; Stahl, Yannick; Joecks, Sebastian; Tran, Cong Si; Lüchtenborg, Christian; V’kovski, Philip; Hörmann, Katrin; Müller, André C.; Zitzmann, Carolin; Haselmann, Uta; Beneke, Jürgen; Kaderali, Lars; Erfle, Holger; Thiel, Volker; Lohmann, Volker; Superti‐Furga, Giulio; Bruegger, Britta; Bartenschlager, Ralf

doi:10.1038/s41467-021-27511-1

Cited by 39 publications

(29 citation statements)

References 62 publications

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“…All these results suggest that SARS-CoV-2 and HCV can exploit autophagosome formation mechanisms to support DMV biogenesis, while blocking lysosome fusion to escape complete autophagy-mediated degradation. These observations reinforce the link between autophagy and DMV formation, revealing unexpected similarities in the mode of operation of two phylogenetically very different viruses [ 39 , 40 ].…”

Section: Introductionsupporting

confidence: 67%

“…The expression of SARS-CoV-2 ORF3a was sufficient to trigger incomplete autophagy, in which autophagosome formation was induced but autophagosome maturation was impaired. It has also been shown that the lipid phosphatidic acid (PA) produced by acylglycerol phosphate acyltransferase (AGPAT) 1 and 2 activity in the ER is essential not only for autophagic vesicle formation, but also for the biogenesis of HCV- and SARS-CoV-2-induced DMVs [ 39 ]. Both these viruses also exploit other common factors involved in autophagosome formation, including class III phosphatidylinositol 3-kinase (PI3K), but without activating conventional autophagy pathways [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

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The double-membrane vesicle (DMV): a virus-induced organelle dedicated to the replication of SARS-CoV-2 and other positive-sense single-stranded RNA viruses

Roingeard

Eymieux

Burlaud‐Gaillard

et al. 2022

Cell. Mol. Life Sci.

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Positive single-strand RNA (+ RNA) viruses can remodel host cell membranes to induce a replication organelle (RO) isolating the replication of their genome from innate immunity mechanisms. Some of these viruses, including severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), induce double-membrane vesicles (DMVs) for this purpose. Viral non-structural proteins are essential for DMV biogenesis, but they cannot form without an original membrane from a host cell organelle and a significant supply of lipids. The endoplasmic reticulum (ER) and the initial mechanisms of autophagic processes have been shown to be essential for the biogenesis of SARS-CoV-2 DMVs. However, by analogy with other DMV-inducing viruses, it seems likely that the Golgi apparatus, mitochondria and lipid droplets are also involved. As for hepatitis C virus (HCV), pores crossing both membranes of SARS-CoV-2-induced DMVs have been identified. These pores presumably allow the supply of metabolites essential for viral replication within the DMV, together with the export of the newly synthesized viral RNA to form the genome of future virions. It remains unknown whether, as for HCV, DMVs with open pores can coexist with the fully sealed DMVs required for the storage of large amounts of viral RNA. Interestingly, recent studies have revealed many similarities in the mechanisms of DMV biogenesis and morphology between these two phylogenetically distant viruses. An understanding of the mechanisms of DMV formation and their role in the infectious cycle of SARS-CoV-2 may be essential for the development of new antiviral approaches against this pathogen or other coronaviruses that may emerge in the future.

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Section: Introductionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

The double-membrane vesicle (DMV): a virus-induced organelle dedicated to the replication of SARS-CoV-2 and other positive-sense single-stranded RNA viruses

Roingeard

Eymieux

Burlaud‐Gaillard

et al. 2022

Cell. Mol. Life Sci.

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“…Several studies have shown the significance of host factors in the RO formation being associated with cell permissiveness and vRNA replication efficiency [17,89,118,126]. For example, Tabata et al (2021) have shown that the RO biogenesis in HCV and SARS-CoV-2 critically depends on the lipid phosphatidic acid synthesis, since inhibiting associated pathways led to an impaired HCV and SARS-CoV-2 RNA replication [136]. However, even though successful in clearing HCV and DENV, in an established infection of a fast-replicating virus such as CVB3, the formation of replicase complexes may not represent an efficient drug target.…”

Section: Discussionmentioning

confidence: 99%

Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies

Zitzmann

Dächert

Schmid

et al. 2022

Preprint

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Plus-strand RNA viruses are the largest group of viruses. Many are human pathogens that inflict a socio-economic burden. Interestingly, plus-strand RNA viruses share remarkable similarities in their replication. A hallmark of plus-strand RNA viruses is the remodeling of intracellular membranes to establish replication organelles (so-called “replication factories”), which provide a protected environment for the replicase complex, consisting of the viral genome and proteins necessary for viral RNA synthesis. In the current study, we investigate pan-viral similarities and virus-specific differences in the life cycle of this highly relevant group of viruses. We first measured the kinetics of viral RNA, viral protein, and infectious virus particle production of hepatitis C virus (HCV), dengue virus (DENV), and coxsackievirus B3 (CVB3) in the immuno-compromised Huh7 cell line and thus without perturbations by an intrinsic immune response. Based on these measurements, we developed a detailed mathematical model of the replication of HCV, DENV, and CVB3 and show that only small virus-specific changes in the model were necessary to describe the in vitro dynamics of the different viruses. Our model correctly predicted virus-specific mechanisms such as host cell translation shut off and different kinetics of replication organelles. Further, our model suggests that the ability to suppress or shut down host cell mRNA translation may be a key factor for in vitro replication efficiency which may determine acute self-limited or chronic infection. We further analyzed potential broad-spectrum antiviral treatment options in silico and found that targeting viral RNA translation, especially polyprotein cleavage, and viral RNA synthesis may be the most promising drug targets for all plus-strand RNA viruses. Moreover, we found that targeting only the formation of replicase complexes did not stop the viral replication in vitro early in infection, while inhibiting intracellular trafficking processes may even lead to amplified viral growth.

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“…The formation of double-membrane vesicles (DMVs) in the host cell induced by SARS-CoV-2 infection, is the first step in replication. NSP3 and NSP4 drive the rearrangement of the endoplasmic reticulum (ER) into DMV and promote genomic RNA (gRNA) and subgenomic RNAs (sgRNAs) replication ( Tabata et al., 2021 ). The viral RNAs are stored in DMVs and transported to the cytosol for translation or through double-membrane-spanning pores for viral assembly ( Zhang and Zhang, 2021 ).…”

Section: The Mechanism Of Sars-cov-2 Infectionmentioning

confidence: 99%

SARS-CoV-2 and Emerging Variants: Unmasking Structure, Function, Infection, and Immune Escape Mechanisms

Jia

Tian

et al. 2022

Front. Cell. Infect. Microbiol.

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As of April 1, 2022, over 468 million COVID-19 cases and over 6 million deaths have been confirmed globally. Unlike the common coronavirus, SARS-CoV-2 has highly contagious and attracted a high level of concern worldwide. Through the analysis of SARS-CoV-2 structural, non-structural, and accessory proteins, we can gain a deeper understanding of structure-function relationships, viral infection mechanisms, and viable strategies for antiviral therapy. Angiotensin-converting enzyme 2 (ACE2) is the first widely acknowledged SARS-CoV-2 receptor, but researches have shown that there are additional co-receptors that can facilitate the entry of SARS-CoV-2 to infect humans. We have performed an in-depth review of published papers, searching for co-receptors or other auxiliary membrane proteins that enhance viral infection, and analyzing pertinent pathogenic mechanisms. The genome, and especially the spike gene, undergoes mutations at an abnormally high frequency during virus replication and/or when it is transmitted from one individual to another. We summarized the main mutant strains currently circulating global, and elaborated the structural feature for increased infectivity and immune evasion of variants. Meanwhile, the principal purpose of the review is to update information on the COVID-19 outbreak. Many countries have novel findings on the early stage of the epidemic, and accruing evidence has rewritten the timeline of the outbreak, triggering new thinking about the origin and spread of COVID-19. It is anticipated that this can provide further insights for future research and global epidemic prevention and control.

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Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation

Cited by 39 publications

References 62 publications

The double-membrane vesicle (DMV): a virus-induced organelle dedicated to the replication of SARS-CoV-2 and other positive-sense single-stranded RNA viruses

The double-membrane vesicle (DMV): a virus-induced organelle dedicated to the replication of SARS-CoV-2 and other positive-sense single-stranded RNA viruses

Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies

SARS-CoV-2 and Emerging Variants: Unmasking Structure, Function, Infection, and Immune Escape Mechanisms

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