title: A nucleotide exchange factor promotes endoplasmic reticulum-to-cytosol membrane penetration of the nonenveloped virus simian virus 40.
abstract: 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.
  
  
  OBJECTIVE
  PyVs 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.
authors: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors: Takamasa
authors: T
authors: Inoue
authors: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA btsai@umich.edu.
authors: Billy
authors: B
authors: Tsai
mesh_terms: D001692:Biological Transport / Q000502:physiology; D003600:Cytosol / Q000378:metabolism* / Q000821:virology; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000821:virology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008156:Luciferases; D016133:Polymerase Chain Reaction; D027601:Polyomavirus Infections / Q000503:physiopathology*; D013539:Simian virus 40 / Q000502:physiology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D020662:Guanine Nucleotide Exchange Factors; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C418483:SIL1 protein, human; C050087:oxygen-regulated proteins; D008156:Luciferases
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