Arenavirus Infection Induces Discrete Cytosolic Structures for RNA Replication

Baird, Nicholas L.; York, Joanne; Nunberg, Jack H.

doi:10.1128/jvi.01635-12

Cited by 74 publications

(85 citation statements)

References 57 publications

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“…Arenavirus replication takes place in the cytoplasm of infected cells. Cell cultures infected with LASV and other arenaviruses typically reveal distinctive intracytoplasmic electron-dense viral inclusions that are suggested to be important sites for RNA replication (Figure 6) [111,112]. Thus, the RNP complex not only has to be recruited from these cytoplasmic locations to virus budding sites at the plasma membrane, but also requires tethering to budding membranes in order to be incorporated into nascent virions.…”

Section: The Multiple Roles Of Z Protein In the Arenavirus Life Cyclementioning

confidence: 99%

Multifunctional Nature of the Arenavirus RING Finger Protein Z

Fehling

Lennartz

Strecker

2012

Viruses

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Arenaviruses are a family of enveloped negative-stranded RNA viruses that can cause severe human disease ranging from encephalitis symptoms to fulminant hemorrhagic fever. The bi‑segmented RNA genome encodes four polypeptides: the nucleoprotein NP, the surface glycoprotein GP, the polymerase L, and the RING finger protein Z. Although it is the smallest arenavirus protein with a length of 90 to 99 amino acids and a molecular weight of approx. 11 kDa, the Z protein has multiple functions in the viral life cycle including (i) regulation of viral RNA synthesis, (ii) orchestration of viral assembly and budding, (iii) interaction with host cell proteins, and (iv) interferon antagonism. In this review, we summarize our current understanding of the structural and functional role of the Z protein in the arenavirus replication cycle.

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Section: The Multiple Roles Of Z Protein In the Arenavirus Life Cyclementioning

confidence: 99%

Multifunctional Nature of the Arenavirus RING Finger Protein Z

Fehling

Lennartz

Strecker

2012

Viruses

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“…Virion NP content was quantitated by sandwich ELISA using MAb AG12 for capture and the noncompeting biotinylated MAb AA10 for detection (40). MAb AA10 was biotinylated using EZ-Link Sulfo-NHS-LC-biotin (sulfosuccinimidyl-6-biotinamido-hexanoate; Life Technologies) and detected with NeutrAvidin-HRP (Pierce) and Sure Blue reagent (KPL).…”

Section: Methodsmentioning

confidence: 99%

Myristoylation of the Arenavirus Envelope Glycoprotein Stable Signal Peptide Is Critical for Membrane Fusion but Dispensable for Virion Morphogenesis

York

Nunberg

2016

J Virol

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Arenaviruses are responsible for severe and often fatal hemorrhagic disease. In the absence of effective antiviral therapies and vaccines, these viruses pose serious threats to public health and biodefense. Arenaviruses enter the host cell by fusion of the viral and endosomal membranes, a process mediated by the virus envelope glycoprotein GPC. Unlike other class I viral fusion proteins, GPC retains its stable signal peptide (SSP) as an essential third subunit in the mature complex. SSP spans the membrane twice and is myristoylated at its cytoplasmic N terminus. Mutations that abolish SSP myristoylation have been shown to reduce pH-induced cell-cell fusion activity of ectopically expressed GPC to ϳ20% of wild-type levels. In order to examine the role of SSP myristoylation in the context of the intact virus, we used reverse genetics to generate Junín viruses (Candid #1 isolate) in which the critical glycine-2 residue in SSP was either replaced by alanine (G2A) or deleted (⌬G2). These mutant viruses produced smaller foci of infection in Vero cells and showed an ϳ5-fold reduction in specific infectivity, commensurate with the defect in cell-cell fusion. However, virus assembly and GPC incorporation into budded virions were unaffected. Our findings suggest that the myristate moiety is cryptically disposed in the prefusion GPC complex and may function late in the fusion process to promote merging of the viral and cellular membranes. IMPORTANCEHemorrhagic fever arenaviruses pose significant threats to public health and biodefense. Arenavirus entry into the host cell is promoted by the virus envelope glycoprotein GPC. Unlike other viral envelope glycoproteins, GPC contains a myristoylated stable signal peptide (SSP) as an essential third subunit. Myristoylation has been shown to be important for the membrane fusion activity of recombinantly expressed GPC. Here, we use reverse genetics to study the role of SSP myristoylation in the context of the intact virion. We find that nonmyristoylated GPC mutants of the Candid #1 strain of Junín virus display a commensurate deficiency in their infectivity, albeit without additional defects in virion assembly and budding. These results suggest that SSP myristoylation may function late in the fusion process to facilitate merging of the viral and cellular membranes. Antiviral agents that target this novel aspect of GPC membrane fusion may be useful in the treatment of arenavirus hemorrhagic fevers.T he mammarenaviruses comprise a diverse genus of enveloped negative-strand RNA viruses whose members have diversified in association with their respective murid hosts (1). Some arenavirus species can be transmitted to humans to cause severe lifethreatening hemorrhagic fevers. Lassa virus (LASV) is endemic in western Africa and can be exported by infected travelers (2-4). Five New World species cause fatal disease in the Americas, including the Argentine hemorrhagic fever virus Junín (JUNV). Frequent reports of new pathogenic isolates suggest a wider diversity of arenavirus species ...

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“…Complete viral genome is also amplified from the agRNA templates. Arenavirus infection induces discrete cytosolic structures for RNA replication [33]. …”

Section: Introductionmentioning

confidence: 99%

Envelope Glycoprotein of Arenaviruses

Burri

Palma

Kunz

et al. 2012

Viruses

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Arenaviruses include lethal human pathogens which pose serious public health threats. So far, no FDA approved vaccines are available against arenavirus infections, and therapeutic options are limited, making the identification of novel drug targets for the development of efficacious therapeutics an urgent need. Arenaviruses are comprised of two RNA genome segments and four proteins, the polymerase L, the envelope glycoprotein GP, the matrix protein Z, and the nucleoprotein NP. A crucial step in the arenavirus life-cycle is the biosynthesis and maturation of the GP precursor (GPC) by cellular signal peptidases and the cellular enzyme Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P) yielding a tripartite mature GP complex formed by GP1/GP2 and a stable signal peptide (SSP). GPC cleavage by SKI-1/S1P is crucial for fusion competence and incorporation of mature GP into nascent budding virion particles. In a first part of our review, we cover basic aspects and newer developments in the biosynthesis of arenavirus GP and its molecular interaction with SKI-1/S1P. A second part will then highlight the potential of SKI-1/S1P-mediated processing of arenavirus GPC as a novel target for therapeutic intervention to combat human pathogenic arenaviruses.

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Arenavirus Infection Induces Discrete Cytosolic Structures for RNA Replication

Cited by 74 publications

References 57 publications

Multifunctional Nature of the Arenavirus RING Finger Protein Z

Multifunctional Nature of the Arenavirus RING Finger Protein Z

Myristoylation of the Arenavirus Envelope Glycoprotein Stable Signal Peptide Is Critical for Membrane Fusion but Dispensable for Virion Morphogenesis

Envelope Glycoprotein of Arenaviruses

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