A Chaperone-Activated Nonenveloped Virus Perforates the Physiologically Relevant Endoplasmic Reticulum Membrane

Rainey-Barger, Emily K.; Magnuson, Brian; Tsai, Billy

doi:10.1128/jvi.01037-07

Cited by 72 publications

(94 citation statements)

References 26 publications

(34 reference statements)

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“…In that regard, HPV16 is unlike adenovirus, which uses the viral protein VI to rupture the endocytic membranes (50). On the other hand, polyomaviruses take advantage of the ER-associated degradation system to translocate across the ER membrane (51,52). Because HPV delays its release until after mitosis and nuclear envelope reformation, it is unlikely to use similar mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Incoming human papillomavirus type 16 genome resides in a vesicular compartment throughout mitosis

DiGiuseppe

Luszczek

Keiffer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

140

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During the entry process, the human papillomavirus (HPV) capsid is trafficked to the trans-Golgi network (TGN), whereupon it enters the nucleus during mitosis. We previously demonstrated that the minor capsid protein L2 assumes a transmembranous conformation in the TGN. Here we provide evidence that the incoming viral genome dissociates from the TGN and associates with microtubules after the onset of mitosis. Deposition onto mitotic chromosomes is L2-mediated. Using differential staining of an incoming viral genome by small molecular dyes in selectively permeabilized cells, nuclease protection, and flotation assays, we found that HPV resides in a membrane-bound vesicle until mitosis is completed and the nuclear envelope has reformed. As a result, expression of the incoming viral genome is delayed. Taken together, these data provide evidence that HPV has evolved a unique strategy for delivering the viral genome to the nucleus of dividing cells. Furthermore, it is unlikely that nuclear vesicles are unique to HPV, and thus we may have uncovered a hitherto unrecognized cellular pathway that may be of interest for future cell biological studies.HPV entry | vesicular transport | mitosis | digitonin | nuclear vesicle A major hurdle of DNA viruses during a primary infection is successful navigation of the cytoplasm to deliver the viral genome to the nucleus. Foreign DNA that enters the cytoplasm is susceptible to being sensed by innate immune sensors (1). Not surprisingly, viruses have evolved mechanisms to evade detection by these sensors. For example, herpesviruses and adenoviruses both egress into the cytoplasm, yet protect their viral DNA by keeping it encased in viral capsids until directly transferring it into the nucleus through the nuclear pore complex. In contrast, the capsid is unlikely to protect papillomavirus (PV) genomes while traversing the cytoplasm, because the major capsid protein is lost in the endocytic compartment (2).The PV capsid is composed of two viral proteins, the major capsid protein L1 and the minor capsid protein L2, which enclose a chromatinized, circular, double-stranded DNA genome ∼8 kb in size (3-6). Following primary attachment and internalization, acidification of early endosomes triggers capsid disassembly (7-22). Host cell cyclophilins release the majority of L1 from the L2 protein, which remains in complex with the viral genome (2,23,24). A large portion of the L2 protein translocates across the endocytic membrane to engage factors, including the retromer complex, dynein, sorting nexins, and rab GTPases, that mediate transport to the trans-Golgi network (TGN) (25)(26)(27)(28)(29)(30)(31)(32)(33)). An siRNA screen has suggested that nuclear pore complexes are not required for nuclear entry, but that nuclear envelope breakdown during mitosis is necessary (34, 35).Currently, when and how the human PV (HPV) genome egresses from the membranous compartment is unclear. Here we present evidence indicating that after the onset of mitosis, the viral genome of HPV type 16 (HPV16), an HPV type...

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Section: Discussionmentioning

confidence: 99%

Incoming human papillomavirus type 16 genome resides in a vesicular compartment throughout mitosis

DiGiuseppe

Luszczek

Keiffer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

140

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“…There it co-opts components of the ERAD machinery to penetrate the ER membrane and reach the cytosol (4,6,14). From the cytosol, the virus enters the nucleus, where ensuing transcription and replication of the viral genome cause lytic infection or cell transformation.In the ER, SV40 hijacks numerous ER chaperones that impart conformational changes to the viral particle to expose its hydrophobic 15). This enables the resulting hydrophobic particle to integrate into and penetrate the ER membrane (4, 15, 16).…”

mentioning

confidence: 99%

A Nucleotide Exchange Factor Promotes Endoplasmic Reticulum-to-Cytosol Membrane Penetration of the Nonenveloped Virus Simian Virus 40

Inoue

Tsai

2015

J Virol

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The nonenveloped simian polyomavirus (PyV) simian virus 40 (SV40) hijacks the endoplasmic reticulum (ER) quality control machinery to penetrate the ER membrane and reach the cytosol, a critical infection step. During entry, SV40 traffics to the ER, where host-induced conformational changes render the virus hydrophobic. The hydrophobic virus binds and integrates into the ER lipid bilayer to initiate membrane penetration. However, prior to membrane transport, the hydrophobic SV40 recruits the ER-resident Hsp70 BiP, which holds the virus in a transport-competent state until it is ready to cross the ER membrane. Here we probed how BiP disengages from SV40 to enable the virus to penetrate the ER membrane. We found that nucleotide exchange factor (NEF) Grp170 induces nucleotide exchange of BiP and releases SV40 from BiP. Importantly, this reaction promotes SV40 ER-to-cytosol transport and infection. The human BK PyV also relies on Grp170 for successful infection. Interestingly, SV40 mobilizes a pool of Grp170 into discrete puncta in the ER called foci. These foci, postulated to represent the ER membrane penetration site, harbor ER components, including BiP, known to facilitate viral ER-to-cytosol transport. Our results thus identify a nucleotide exchange activity essential for catalyzing the most proximal event before ER membrane penetration of PyVs. IMPORTANCEPyVs are known to cause debilitating human diseases. During entry, this virus family, including monkey SV40 and human BK PyV, hijacks ER protein quality control machinery to breach the ER membrane and access the cytosol, a decisive infection step. In this study, we pinpointed an ER-resident factor that executes a crucial role in promoting ER-to-cytosol membrane penetration of PyVs. Identifying a host factor that facilitates entry of the PyV family thus provides additional therapeutic targets to combat PyV-induced diseases. Pathogens hijack protein quality control pathways of host cells to successfully cause infection. One pathway co-opted by pathogens during entry is endoplasmic reticulum (ER)-associated degradation (ERAD) (1-3). While ERAD is a surveillance system normally dedicated to the removal of misfolded ER proteins to the cytosol for proteasomal destruction, pathogens can co-opt elements of this pathway to gain entry into the host cytosol by disguising themselves as misfolded ER proteins. A clearer picture of the nature of this pathogen-host interaction is slowly emerging.Entry of the nonenveloped polyomavirus (PyV) family, including the simian virus 40 (SV40) and the human BK PyVs, serves as a salient example of pathogens that co-opt the ERAD pathway during infection (4-6). Structurally, SV40 is composed of 360 copies of the VP1 major coat protein arranged as 72 pentamers, with each pentamer engaging either the VP2 or VP3 internal hydrophobic minor coat protein. The pentamers are assembled as a 45-nm-diameter icosahedral particle that in turn encapsulates its viral DNA genome (7,8). To infect cells, SV40 undergoes receptor-mediated endocytosis a...

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“…ERp29, structurally related to PDI protein (Mkrtchian et al 1998), acts as a factor in inducing a conformational change in PyV particles by exposing the C-terminus of VP1 protein without the complete disintegration of the virion structure (Magnuson et al 2005). Portions of VP2 and VP3 are also exposed that mediate the binding to the ER membrane, although only VP2 can perforate the experimental model membranes (Rainey-Barger et al 2007).…”

Section: Er-mediated Viral Traffickingmentioning

confidence: 99%

“…However, the precise combination of PDI members engaging a specific PyV family member may differ because of subtle differences in the viral disulfide bond arrangements. In some PyVs, a dimeric redox-inactive PDI protein (ERp29) untangles the VP1 carboxy-terminal arms exposing hydrophobic VP2 and VP3 to generate a hydrophobic viral particle (Magnuson et al 2005;Rainey-Barger et al 2007). The hydrophobic virus is probably maintained in a soluble state by binding to the Hsp70 chaperone BiP in a reaction regulated by the J domain containing co-chaperone ERdj3 (Goodwin et al 2011).…”

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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A Chaperone-Activated Nonenveloped Virus Perforates the Physiologically Relevant Endoplasmic Reticulum Membrane

Cited by 72 publications

References 26 publications

Incoming human papillomavirus type 16 genome resides in a vesicular compartment throughout mitosis

Incoming human papillomavirus type 16 genome resides in a vesicular compartment throughout mitosis

A Nucleotide Exchange Factor Promotes Endoplasmic Reticulum-to-Cytosol Membrane Penetration of the Nonenveloped Virus Simian Virus 40

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

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