Untangling Membrane Rearrangement in the<i>Nidovirales</i>

Angelini, Megan M.; Neuman, Benjamin W.; Buchmeier, Michael J.

doi:10.1089/dna.2013.2304

Cited by 24 publications

(28 citation statements)

References 72 publications

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“…Positive-strand RNA viruses coopt intracellular membranes of the host cell in which the viral replication machineries are anchored and protected from degradative enzymes and from detection by the host's immune system. Members of the order Nidovirales induce formation of double-membrane vesicles (DMVs) and convoluted membranes (CMs) that are essential for viral replication and progeny production (13). Although ultrastructural analyses suggested that the ER is the source of the DMVs and CMs, no conventional ER markers could be detected, leaving the origin and composition of these structures mysterious.…”

Section: Erad Tuning Vesicles As Scaffold For Positive-strand Rna Virmentioning

confidence: 99%

“…As nsp3, -4, and -6 of CoVs and their EAV homologues nsp2, -3, and -5 are synthesized in the ER and are essential for DMV formation, it has been assumed that these proteins can cause ER membrane rearrangements. Individual expression of these nsp reveals DMV intermediates, such as proliferated membranes (nsp3), a vesiculated ER (nsp6), or paired ER membranes (nsp3 and nsp4) (13). Ultrastructural characterization of the paired ER membranes induced by a truncated version of nsp3 and nsp4 demonstrated that these proteins induce ER membrane curvature (17).…”

Section: Putative Role Of Viral Nonstructural Proteins In the Subversmentioning

confidence: 99%

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How Viruses Hijack the ERAD Tuning Machinery

Noack¹,

Bernasconi²,

Molinari

2014

J Virol

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An essential step during the intracellular life cycle of many positive-strand RNA viruses is the rearrangement of host cell membranes to generate membrane-bound replication platforms. For example, Nidovirales and Flaviviridae subvert the membrane of the endoplasmic reticulum (ER) for their replication. However, the absence of conventional ER and secretory pathway markers in virus-induced ER-derived membranes has for a long time hampered a thorough understanding of their biogenesis. Recent reports highlight the analogies between mouse hepatitis virus-, equine arteritis virus-, and Japanese encephalitis virus-induced replication platforms and ER-associated degradation (ERAD) tuning vesicles (or EDEMosomes) that display nonlipidated LC3 at their cytosolic face and segregate the ERAD factors EDEM1, OS-9, and SEL1L from the ER lumen. In this Gem, we briefly summarize the current knowledge on ERAD tuning pathways and how they might be hijacked for viral genome replication. As ERAD tuning components, such as SEL1L and nonlipidated LC3, appear to contribute to viral infection, these cellular pathways represent novel candidate drug targets to combat positive-strand RNA viruses. QUALITY CONTROL OPERATING IN THE ENDOPLASMIC RETICULUM Secreted and membrane proteins are synthesized, folded, and assembled in the endoplasmic reticulum (ER). Acquisition of the native protein structure is assisted by a broad spectrum of resident molecular chaperones and folding enzymes that catalyze rate-limiting reactions, such as the formation of the correct configuration of disulfide and peptidyl-prolyl bonds. A dedicated quality control system ensures that only correctly folded and assembled proteins leave the ER and are transported along the secretory pathway to reach their final destination. Misfolded proteins are retrotranslocated (dislocated) into the cytosol, polyubiquitylated, and then degraded by 26S proteasomes, a process known as ER-associated degradation (ERAD) (1). FOLDING AND ERAD IN THE BALANCEThe ERAD machinery can hardly distinguish nonnative intermediates of ongoing folding programs (which should be preserved) from nonnative side products of the folding process (which should be eliminated). As such, hyper-ERAD may result in lossof-function phenotypes upon inappropriate degradation of folding intermediates, whereas hypo-ERAD may cause gain-of-toxicfunction phenotypes upon accumulation of misfolded proteins. Therefore, a tight regulation of the ERAD capacity and its prompt adaptation to fluctuations in the ER cargo load is crucial to maintain cellular proteostasis. To large or prolonged variations of ER homeostasis (e.g., upon differentiation in highly secretory cells, exposure to drugs affecting sugar, calcium or redox homeostasis, widespread accumulation of misfolded polypeptides, challenges with pathogen) cells may respond by induction of the unfolded protein response (UPR) that consists in enhanced transcription/ translation of ER-resident folding and degradation factors and expansion of the ER volume. Smaller or mo...

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Section: Erad Tuning Vesicles As Scaffold For Positive-strand Rna Virmentioning

confidence: 99%

Section: Putative Role Of Viral Nonstructural Proteins In the Subversmentioning

confidence: 99%

How Viruses Hijack the ERAD Tuning Machinery

Noack¹,

Bernasconi²,

Molinari

2014

J Virol

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“…Phylogenetic analysis further showed that this foreign PLP forms a well-supported clade with PLPs of other toroviruses, including bovine, porcine, and equine toroviruses ( Fig. 3) (40,41). We designated this foreign gene ToV-PLP.…”

Section: Resultsmentioning

confidence: 96%

A Naturally Occurring Recombinant Enterovirus Expresses a Torovirus Deubiquitinase

Shang

Misra

Hause

et al. 2017

J Virol

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Enteroviruses (EVs) are implicated in a wide range of diseases in humans and animals. In this study, a novel enterovirus (enterovirus species G [EVG]) (EVG 08/NC_USA/2015) was isolated from a diagnostic sample from a neonatal pig diarrhea case and identified by using metagenomics and complete genome sequencing. The viral genome shares 75.4% nucleotide identity with a prototypic EVG strain (PEV9 UKG/410/73). Remarkably, a 582-nucleotide insertion, flanked by 3C pro cleavage sites at the 5= and 3= ends, was found in the 2C/3A junction region of the viral genome. This insertion encodes a predicted protease with 54 to 68% amino acid identity to torovirus (ToV) papain-like protease (PLP) (ToV-PLP). Structural homology modeling predicts that this protease adopts a fold and a catalytic site characteristic of minimal PLP catalytic domains. This structure is similar to those of core catalytic domains of the foot-and-mouth disease virus leader protease and coronavirus PLPs, which act as deubiquitinating and deISGylating (interferon [IFN]-stimulated gene 15 [ISG15]-removing) enzymes on host cell substrates. Importantly, the recombinant ToV-PLP protein derived from this novel enterovirus also showed strong deubiquitination and deISGylation activities and demonstrated the ability to suppress IFN-␤ expression. Using reverse genetics, we generated a ToV-PLP knockout recombinant virus. Compared to the wild-type virus, the ToV-PLP knockout mutant virus showed impaired growth and induced higher expression levels of innate immune genes in infected cells. These results suggest that ToV-PLP functions as an innate immune antagonist; enterovirus G may therefore gain fitness through the acquisition of ToV-PLP from a recombination event.IMPORTANCE Enteroviruses comprise a highly diversified group of viruses. Genetic recombination has been considered a driving force for viral evolution; however, recombination between viruses from two different orders is a rare event. In this study, we identified a special case of cross-order recombination between enterovirus G (order Picornavirales) and torovirus (order Nidovirales). This naturally occurring recombination event may have broad implications for other picornaviral and/or nidoviral species. Importantly, we demonstrated that the exogenous ToV-PLP gene that was inserted into the EVG genome encodes a deubiquitinase/ deISGylase and potentially suppresses host cellular innate immune responses. Our results provide insights into how a gain of function through genetic recombination, in particular cross-order recombination, may improve the ability of a virus to evade host immunity.KEYWORDS enterovirus G, torovirus, genetic recombination, papain-like protease, deubiquitinase

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“…1. The common element in nidovirus-like membrane rearrangement is that the membranes are paired, usually maintaining a consistent-sized gap between the two membranes (reviewed here, Angelini et al, 2014). Since protein-induced membrane Fig.…”

Section: Structure Of the Organellesmentioning

confidence: 99%

New insights on the role of paired membrane structures in coronavirus replication

et al. 2015

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The replication of coronaviruses, as in other positive-strand RNA viruses, is closely tied to the formation of membrane-bound replicative organelles inside infected cells. The proteins responsible for rearranging cellular membranes to form the organelles are conserved not just among the Coronaviridae family members, but across the order Nidovirales. Taken together, these observations suggest that the coronavirus replicative organelle plays an important role in viral replication, perhaps facilitating the production or protection of viral RNA. However, the exact nature of this role, and the specific contexts under which it is important have not been fully elucidated. Here, we collect and interpret the recent experimental evidence about the role and importance of membrane-bound organelles in coronavirus replication.

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Untangling Membrane Rearrangement in theNidovirales

Cited by 24 publications

References 72 publications

How Viruses Hijack the ERAD Tuning Machinery

How Viruses Hijack the ERAD Tuning Machinery

A Naturally Occurring Recombinant Enterovirus Expresses a Torovirus Deubiquitinase

New insights on the role of paired membrane structures in coronavirus replication

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