EMC1-dependent stabilization drives membrane penetration of a partially destabilized non-enveloped virus

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Abstract

Destabilization of a non-enveloped virus generates a membrane transport-competent viral particle. Here we probe polyomavirus SV40 endoplasmic reticulum (ER)-to-cytosol membrane transport, a decisive infection step where destabilization initiates this non-enveloped virus for membrane penetration. We find that a member of the ER membrane protein complex (EMC) called EMC1 promotes SV40 ER membrane transport and infection. Surprisingly, EMC1 does so by using its predicted transmembrane residue D961 to bind to and stabilize the membrane-embedded partially destabilized SV40, thereby preventing premature viral disassembly. EMC1-dependent stabilization enables SV40 to engage a cytosolic extraction complex that ejects the virus into the cytosol. Thus EMC1 acts as a molecular chaperone, bracing the destabilized SV40 in a transport-competent state. Our findings reveal the novel principle that coordinated destabilization-stabilization drives membrane transport of a non-enveloped virus.

DOI: http://dx.doi.org/10.7554/eLife.21470.001

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ER-associated degradation: Protein quality control and beyond

Annamaria Ruggiano, Ombretta Foresti, Pedro Boal Carvalho (2014)

Even with the assistance of many cellular factors, a significant fraction of newly synthesized proteins ends up misfolded. Cells evolved protein quality control systems to ensure that these potentially toxic species are detected and eliminated. The best characterized of these pathways, the ER-associated protein degradation (ERAD), monitors the folding of membrane and secretory proteins whose biogenesis takes place in the endoplasmic reticulum (ER). There is also increasing evidence that ERAD controls other ER-related functions through regulated degradation of certain folded ER proteins, further highlighting the role of ERAD in cellular homeostasis.

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Defining human ERAD networks through an integrative mapping strategy

John C Christianson, James A. Olzmann, Thomas Shaler … (2011)

SUMMARY Proteins that fail to correctly fold or assemble into oligomeric complexes in the endoplasmic reticulum (ER) are degraded by a ubiquitin and proteasome dependent process known as ER-associated degradation (ERAD). Although many individual components of the ERAD system have been identified, how these proteins are organised into a functional network that coordinates recognition, ubiquitination, and dislocation of substrates across the ER membrane is not well understood. We have investigated the functional organisation of the mammalian ERAD system using a systems-level strategy that integrates proteomics, functional genomics, and the transcriptional response to ER stress. This analysis supports an adaptive organisation for the mammalian ERAD machinery and reveals a number of metazoan-specific genes not previously linked to ERAD.

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Adenovirus protein VI mediates membrane disruption following capsid disassembly.

Christopher Wiethoff, Harald Wodrich, Glen Nemerow … (2005)

In contrast to enveloped viruses, the mechanisms involved in membrane penetration by nonenveloped viruses are not as well understood. In these studies, we determined the relationship between adenovirus (Ad) capsid disassembly and the development of membrane lytic activity. Exposure to low pH or heating induced conformational changes in wild-type Ad but not in temperature-sensitive Ad (ts1) particles that fail to escape the early endosome. Wild-type Ad but not ts1 particles permeabilized model membranes (liposomes) and facilitated the cytosolic delivery of a ribotoxin. Alterations in wild-type Ad capsids were associated with the exposure of a pH-independent membrane lytic factor. Unexpectedly, this factor was identified as protein VI, a 22-kDa cement protein located beneath the peripentonal hexons in the viral capsid. Recombinant protein VI and preprotein VI, but not a deletion mutant lacking an N-terminal amphipathic alpha-helix, possessed membrane lytic activity similar to partially disassembled virions. A new model of Ad entry is proposed based on our present observations of capsid disassembly and membrane penetration.

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Author and article information

Contributors

Ramanujan S Hegde: Role: Reviewing editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (hwp): eLife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 24 December 2016

Publication date Collection: 2016

Volume: 5

Electronic Location Identifier: e21470

Affiliations

[1 ]deptDepartment of Cell and Developmental Biology , University of Michigan Medical School , Ann Arbor, United States

[2]MRC Laboratory of Molecular Biology , United Kingdom

[3]MRC Laboratory of Molecular Biology , United Kingdom

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btsai@ 123456umich.edu

Author information

Billy Tsai http://orcid.org/0000-0003-2859-1415

Article

Publisher ID: 21470

DOI: 10.7554/eLife.21470

PMC ID: 5224922

PubMed ID: 28012275

SO-VID: 628575d4-5514-4625-9db3-e81eef52902d

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This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 13 September 2016

Date accepted : 23 December 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: AI064296

Award Recipient : Billy Tsai

Funded by: FundRef http://dx.doi.org/10.13039/100007270, University of Michigan;

Award ID: Protein Folding Disease Initiative, University Funds

Award Recipient : Billy Tsai

Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;

Award ID: GM113722

Award Recipient : Billy Tsai

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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Author impact statement Biochemical and cell-based analyses reveal how a non-enveloped virus exploits the chaperone activity of an ER transmembrane protein to penetrate the ER membrane required for successful virus infection.

ScienceOpen disciplines: Life sciences

Keywords: protein stabilization,membrane transport,viral entry,human

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ScienceOpen disciplines: Life sciences

Keywords: protein stabilization, membrane transport, viral entry, human

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EMC1-dependent stabilization drives membrane penetration of a partially destabilized non-enveloped virus

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Most cited references 36

ER-associated degradation: Protein quality control and beyond

Defining human ERAD networks through an integrative mapping strategy

Adenovirus protein VI mediates membrane disruption following capsid disassembly.

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Cited by 31

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