Protein disulfide isomerases contribute differentially to the endoplasmic reticulum–associated degradation of apolipoprotein B and other substrates

Grubb, Sarah R.; Guo, Liang; Fisher, Edward A.; Brodsky, Jeffrey L.

doi:10.1091/mbc.e11-08-0704

Cited by 60 publications

(71 citation statements)

References 125 publications

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“…This result indicates that PDI does not function as a reductase against SV40, in contrast to its action on murine PyV (11). Instead, in addition to its enzymatic function, PDI is also known to possess a chaperone activity, unfolding ERAD substrates and the bacterial cholera toxin prior to retrotranslocation to the cytosol (47)(48)(49)(50). If PDI's unfoldase activity operates on SV40, how then might this activity cooperate with ERdj5 to regulate SV40 ER-to-cytosol transport?…”

Section: Discussionmentioning

confidence: 98%

ERdj5 Reductase Cooperates with Protein Disulfide Isomerase To Promote Simian Virus 40 Endoplasmic Reticulum Membrane Translocation

Inoue

Dosey

Herbstman

et al. 2015

J Virol

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The nonenveloped polyomavirus (PyV) simian virus 40 (SV40) traffics from the cell surface to the endoplasmic reticulum (ER), where it penetrates the ER membrane to reach the cytosol before mobilizing into the nucleus to cause infection. Prior to ER membrane penetration, ER lumenal factors impart structural rearrangements to the virus, generating a translocation-competent virion capable of crossing the ER membrane. Here we identify ERdj5 as an ER enzyme that reduces SV40's disulfide bonds, a reaction important for its ER membrane transport and infection. ERdj5 also mediates human BK PyV infection. This enzyme cooperates with protein disulfide isomerase (PDI), a redox chaperone previously implicated in the unfolding of SV40, to fully stimulate membrane penetration. Negative-stain electron microscopy of ER-localized SV40 suggests that ERdj5 and PDI impart structural rearrangements to the virus. These conformational changes enable SV40 to engage BAP31, an ER membrane protein essential for supporting membrane penetration of the virus. Uncoupling of SV40 from BAP31 traps the virus in ER subdomains called foci, which likely serve as depots from where SV40 gains access to the cytosol. Our study thus pinpoints two ER lumenal factors that coordinately prime SV40 for ER membrane translocation and establishes a functional connection between lumenal and membrane events driving this process. IMPORTANCE PyVs are established etiologic agents of many debilitating human diseases, especially in immunocompromised individuals. To infect cells at the cellular level, this virus family must penetrate the host ER membrane to reach the cytosol, a critical entry step.In this report, we identify two ER lumenal factors that prepare the virus for ER membrane translocation and connect these lumenal events with events on the ER membrane. Pinpointing cellular components necessary for supporting PyV infection should lead to rational therapeutic strategies for preventing and treating PyV-related diseases. Viruses must penetrate host cell membranes to reach their proper intracellular destination where they replicate their genome, producing viral progenies used for the next round of infection. While enveloped viruses breach host cells by fusing their membrane with a target cell membrane, the mechanism by which nonenveloped viruses penetrate the host cell membrane must be distinct from that of enveloped viruses, as they lack a surrounding membrane. Despite being poorly characterized, a series of biochemical experiments provided a general model describing nonenveloped virus membrane penetration (1-5). In this model, the nonenveloped virus first traffics to the proper site for membrane penetration. Here the viral particle undergoes defined conformational changes induced by host environments and factors (e.g., low pH, proteases, reductases, and chaperones) that either expose hydrophobic moieties buried in the native virus or release small lytic peptides hidden in the intact virion (1-11). In the final step, the hydrophobic viral intermediate (o...

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Section: Discussionmentioning

confidence: 98%

ERdj5 Reductase Cooperates with Protein Disulfide Isomerase To Promote Simian Virus 40 Endoplasmic Reticulum Membrane Translocation

Inoue

Dosey

Herbstman

et al. 2015

J Virol

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“…We have successfully applied our approach to varied substrates including: CFTR (50,54,66,79), apolipoprotein B (80,81), antitrypsin-Z (82)(83)(84), and the sodium chloride cotransporter (51). In each case yeast model studies have led us to identify conserved, human homologs of chaperones and chaperone-like proteins that impact the ERAD of these substrates in higher eukaryotes.…”

Section: Discussionmentioning

confidence: 99%

The Lhs1/GRP170 Chaperones Facilitate the Endoplasmic Reticulum-associated Degradation of the Epithelial Sodium Channel

Buck

Plavchak

Roy

et al. 2013

Journal of Biological Chemistry

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Background:The epithelial sodium channel (ENaC) is a substrate for the endoplasmic reticulum associated degradation (ERAD) quality control system. Results: The chaperone Lhs1/GRP170 selects the nonglycosylated form of the ␣ subunit for ERAD. Conclusion: This study is the first to show a role for Lhs1/GRP170 in ERAD substrate selection. Significance: Mutations in ENaC are associated with human disease; therefore, Lhs1/GRP170, as a modulator of ENaC expression, may be a target for new therapeutic agents.

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“…These enzymes could therefore be present in the endosomal compartment, with small amounts being taken up from the surface during endocytosis. PDI family members have independent, overlapping, and cooperative substrate specificity and can exist within multiprotein complexes composed of various PDIs, molecular chaperones, and ER stress proteins (24,42,59,76,82). It remains to be determined if PDI and ERp72 directly interact with HPV16 and are direct targets of Bac or whether PDI and ERp72 act in a redox network upstream of a cellular reductase to modulate HPV16 infection.…”

Section: Discussionmentioning

confidence: 99%

Opposing Effects of Bacitracin on Human Papillomavirus Type 16 Infection: Enhancement of Binding and Entry and Inhibition of Endosomal Penetration

Campos

Chapman

Deymier

et al. 2012

J Virol

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e Cell invasion by human papillomavirus type 16 (HPV16) is a complex process relying on multiple host cell factors. Here we describe an investigation into the role of cellular protein disulfide isomerases (PDIs) by studying the effects of the commonly used PDI inhibitor bacitracin on HPV16 infection. Bacitracin caused an unusual time-dependent opposing effect on viral infection. Enhanced cellular binding and entry were observed at early times of infection, while inhibition was observed at later times postentry. Bacitracin was rapidly taken up by host cells and colocalized with HPV16 at late times of infection. Bacitracin had no deleterious effect on HPV16 entry, capsid disassembly, exposure of L1/L2 epitopes, or lysosomal trafficking but caused a stark inhibition of L2/viral DNA (vDNA) endosomal penetration and accumulation at nuclear PML bodies. ␥-Secretase has recently been implicated in the endosomal penetration of L2/vDNA, but bacitracin had no effect on ␥-secretase activity, indicating that blockage of this step occurs through a ␥-secretase-independent mechanism. Transient treatment with the reductant ␤-mercaptoethanol (␤-ME) was able to partially rescue the virus from bacitracin, suggesting the involvement of a cellular reductase activity in HPV16 infection. Small interfering RNA (siRNA) knockdown of cellular PDI and the related PDI family members ERp57 and ERp72 reveals a potential role for PDI and ERp72 in HPV infection. Human papillomaviruses (HPVs) are one of the most common sexually transmitted infections in the world. HPVs are small 55-nm icosahedral nonenveloped double-stranded DNA (dsDNA) viruses that replicate in differentiating cutaneous and mucosal epithelium. Infection of mucosal epithelium by oncogenic HPV genotypes can lead to cervical, anogenital, and other head and neck cancers. HPV type 16 (HPV16) is the most common of the high-risk types and is alone responsible for over 50% of cervical cancers worldwide (77). Although HPVs have been known to be the etiological agent of cervical cancer for nearly 30 years, and despite intensive research in recent years, the infectious entry pathway of HPV16 is still not well defined. Our current understanding of HPV cellular invasion reveals a complex and prolonged process, complicated by differences between in vitro cell culture systems and the recently described in vivo mouse cervicovaginal challenge model (33,37,50,62).The HPV capsid is assembled from 360 molecules of the L1 protein, arranged as 72 pentamers. L1 monomers from neighboring pentamers are disulfide bonded to each other as dimers and trimers, providing stability to the capsid (45). The minor capsid protein L2 is localized within a central cavity beneath the L1 pentamers. L2 can be present at a maximum stoichiometry of one L2 molecule per L1 pentamer or 72 molecules per virion; however, most preparations of virus contain submaximal levels of L2, typically 20 to 25 copies per virion (6). Packaged within the capsid is the ϳ8-kb viral genome (viral DNA [vDNA]), condensed as chromatin with cellu...

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Protein disulfide isomerases contribute differentially to the endoplasmic reticulum–associated degradation of apolipoprotein B and other substrates

Cited by 60 publications

References 125 publications

ERdj5 Reductase Cooperates with Protein Disulfide Isomerase To Promote Simian Virus 40 Endoplasmic Reticulum Membrane Translocation

ERdj5 Reductase Cooperates with Protein Disulfide Isomerase To Promote Simian Virus 40 Endoplasmic Reticulum Membrane Translocation

The Lhs1/GRP170 Chaperones Facilitate the Endoplasmic Reticulum-associated Degradation of the Epithelial Sodium Channel

Opposing Effects of Bacitracin on Human Papillomavirus Type 16 Infection: Enhancement of Binding and Entry and Inhibition of Endosomal Penetration

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