Role of Cell-Type-Specific Endoplasmic Reticulum-Associated Degradation in Polyomavirus Trafficking

Bennett, Shauna M.; Jiang, Mengxi; Imperiale, Michael J.

doi:10.1128/jvi.00664-13

Cited by 47 publications

(61 citation statements)

References 38 publications

(63 reference statements)

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“…Several host components required by PyVs for infection are implicated in ERAD, including BAP31, B12, and B14 (23)(24)(25)(26)(27)(28)(29)(30)34). However, the precise functions of these proteins in ERAD are not clear, and whether C18 participates in ERAD is completely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…ERAD is a quality control process that functions to eliminate misfolded proteins from the ER by retrotranslocating them into cytosol for proteasomal degradation (24). SV40 and other PyVs utilize selective ERAD components, as well as the ER membrane-bound J proteins DnaJB12 (B12), DnaJB14 (B14), and DnaJC18 (C18), to reach the cytosol and cause infection (23)(24)(25)(26)(27)(28)(29)(30). The individual contribution of each membrane-bound J protein, their potential redundancy, and how they may cooperate to promote successful PyV membrane penetration and infection are largely unknown.…”

mentioning

confidence: 99%

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The Endoplasmic Reticulum Membrane J Protein C18 Executes a Distinct Role in Promoting Simian Virus 40 Membrane Penetration

Bagchi

Walczak

Tsai

2015

J Virol

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The nonenveloped simian virus 40 (SV40) hijacks the three endoplasmic reticulum (ER) membrane-bound J proteins B12, B14, and C18 to escape from the ER into the cytosol en route to successful infection. How C18 controls SV40 ER-to-cytosol membrane penetration is the least understood of these processes. We previously found that SV40 triggers B12 and B14 to reorganize into discrete puncta in the ER membrane called foci, structures postulated to represent the cytosol entry site (C. P. Walczak, M. S. Ravindran, T. Inoue, and B. Tsai, PLoS Pathog 10:e1004007, 2014). We now find that SV40 also recruits C18 to the virus-induced B12/B14 foci. Importantly, the C18 foci harbor membrane penetration-competent SV40, further implicating this structure as the membrane penetration site. Consistent with this, a mutant SV40 that cannot penetrate the ER membrane and promote infection fails to induce C18 foci. C18 also regulates the recruitment of B12/B14 into the foci. In contrast to B14, C18's cytosolic Hsc70-binding J domain, but not the lumenal domain, is essential for its targeting to the foci; this J domain likewise is necessary to support SV40 infection. Knockdown-rescue experiments reveal that C18 executes a role that is not redundant with those of B12/B14 during SV40 infection. Collectively, our data illuminate C18's contribution to SV40 ER membrane penetration, strengthening the idea that SV40-triggered foci are critical for cytosol entry. IMPORTANCEPolyomaviruses (PyVs) cause devastating human diseases, particularly in immunocompromised patients. As this virus family continues to be a significant human pathogen, clarifying the molecular basis of their cellular entry pathway remains a high priority. To infect cells, PyV traffics from the cell surface to the ER, where it penetrates the ER membrane to reach the cytosol. In the cytosol, the virus moves to the nucleus to cause infection. ER-to-cytosol membrane penetration is a critical yet mysterious infection step. In this study, we clarify the role of an ER membrane protein called C18 in mobilizing the simian PyV SV40, a PyV archetype, from the ER into the cytosol. Our findings also support the hypothesis that SV40 induces the formation of punctate structures in the ER membrane, called foci, that serve as the portal for cytosol entry of the virus. While polyomaviruses (PyVs) are known to establish asymptomatic persistent infections in the kidney, blood, skin, and brain of healthy individuals, they carry the potential to cause debilitating diseases, especially during immunosuppression. For example, infections caused by the human BK, JC, and Merkel cell PyVs can lead to PyV-associated nephropathy, progressive multifocal leukoencephalopathy, and Merkel cell carcinoma, respectively (1, 2). Simian virus 40 (SV40) traditionally has been used as a model for studying this virus family and has structural and genetic similarities to human PyVs. SV40 and all other PyVs are nonenveloped icosahedral particles, approximately 45 nm in diameter, and contain a double-stranded DNA gen...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Endoplasmic Reticulum Membrane J Protein C18 Executes a Distinct Role in Promoting Simian Virus 40 Membrane Penetration

Bagchi

Walczak

Tsai

2015

J Virol

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“…The outer layer of the viral particle is made up of 72 VP1 pentamers stabilized by intermolecular disulfide bonds (Nilsson et al, 2005). Associated with each pentamer is one molecule of either VP2 or VP3, which are not exposed to the surface of the particle until disassembly begins within the endoplasmic reticulum (ER) of the host cell (Bennett et al, 2013). VP2 and VP3 are expressed from the same reading frame and share an identical C-terminus, but VP2 contains a unique N-terminal sequence that can be myristoylated (Krauzewicz et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Role of a nuclear localization signal on the minor capsid Proteins VP2 and VP3 in BKPyV nuclear entry

et al. 2015

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BK Polyomavirus (BKPyV) is a ubiquitous nonenveloped human virus that can cause severe disease in immunocompromised populations. After internalization into renal proximal tubule epithelial cells, BKPyV traffics through the ER and enters the cytosol. However, it is unclear how the virus enters the nucleus. In this study, we elucidate a role for the nuclear localization signal located on the minor capsid proteins VP2 and VP3 during infection. Site-directed mutagenesis of a single lysine in the basic region of the C-terminus of the minor capsid proteins abrogated their nuclear localization, and the analogous genomic mutation reduced infectivity. Additionally, through use of the inhibitor ivermectin and knockdown of importin β1, we found that the importin α/β pathway is involved during infection. Overall these data are the first to show the significance of the NLS of the BKPyV minor capsid proteins during infection in a natural host cell.

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“…Transfection of the dominant-negative ER-transmembrane proteins Derlin-1 and Derlin-2 in RPTE cells and glutathione S-transferase pull-down assays revealed the involvement of Derlin-1, but not Derlin-2, in BKPyV escape from the ER to the cytosol Bennett et al 2013). Proteasome function was also indicated in successful BKPyV trafficking, like SV40, in proteasome inhibition assays (Bennett et al 2013). …”

Section: Er-mediated Viral Traffickingmentioning

confidence: 99%

“…The ERAD pathway during BKPyV intracellular trafficking has been studied in renal proximal tubule epithelial (RPTE) cells using proteasome and ERAD inhibitors Bennett et al 2013). Transfection of the dominant-negative ER-transmembrane proteins Derlin-1 and Derlin-2 in RPTE cells and glutathione S-transferase pull-down assays revealed the involvement of Derlin-1, but not Derlin-2, in BKPyV escape from the ER to the cytosol Bennett et al 2013).…”

Section: Er-mediated Viral Traffickingmentioning

confidence: 99%

Entry, infection, replication, and egress of human polyomaviruses: an update

Bhattacharjee

Chattaraj

2017

Can. J. Microbiol.

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Polyomaviruses (PyVs), belonging to the family Polyomaviridae, are a group of small, nonenveloped, double-stranded, circular DNA viruses widely distributed in the vertebrates. PyVs cause no apparent disease in adult laboratory mice but cause a wide variety of tumors when artificially inoculated into neonates or semipermissive animals. A few human PyVs, such as BK, JC, and Merkel cell PyVs, have been unequivocally linked to pathogenesis under conditions of immunosuppression. Infection is thought to occur early in life and persists for the lifespan of the host. Over evolutionary time scales, it appears that PyVs have slowly co-evolved with specific host animal lineages. Host cell surface glycoproteins and glycolipids seem to play a decisive role in the entry stage of viral infection and in channeling the virions to specific intracellular membrane-bound compartments and ultimately to the nucleus, where the genomes are replicated and packaged for release. Therefore the transport of the infecting virion or viral genome to this site of multiplication is an essential process in productive viral infection as well as in latent infection and transformation. This review summarizes the major findings related to the characterization of the nature of the interactions between PyV and host protein and their impact in host cell invasion.

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Role of Cell-Type-Specific Endoplasmic Reticulum-Associated Degradation in Polyomavirus Trafficking

Cited by 47 publications

References 38 publications

The Endoplasmic Reticulum Membrane J Protein C18 Executes a Distinct Role in Promoting Simian Virus 40 Membrane Penetration

The Endoplasmic Reticulum Membrane J Protein C18 Executes a Distinct Role in Promoting Simian Virus 40 Membrane Penetration

Role of a nuclear localization signal on the minor capsid Proteins VP2 and VP3 in BKPyV nuclear entry

Entry, infection, replication, and egress of human polyomaviruses: an update

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