title: The Grp170 nucleotide exchange factor executes a key role during ERAD of cellular misfolded clients.
abstract: When a protein misfolds in the endoplasmic reticulum (ER), it retrotranslocates to the cytosol and is degraded by the proteasome via a pathway called ER-associated degradation (ERAD). To initiate ERAD, ADP-BiP is often recruited to the misfolded client, rendering it soluble and translocation competent. How the misfolded client is subsequently released from BiP so that it undergoes retrotranslocation, however, remains enigmatic. Here we demonstrate that the ER-resident nucleotide exchange factor (NEF) Grp170 plays an important role during ERAD of the misfolded glycosylated client null Hong Kong (NHK). As a NEF, Grp170 triggers nucleotide exchange of BiP to generate ATP-BiP. ATP-BiP disengages from NHK, enabling it to retrotranslocate to the cytosol. We demonstrate that Grp170 binds to Sel1L, an adapter of the transmembrane Hrd1 E3 ubiquitin ligase postulated to be the retrotranslocon, and links this interaction to Grp170's function during ERAD. More broadly, Grp170 also promotes degradation of the nonglycosylated transthyretin (TTR) D18G misfolded client. Our findings thus establish a general function of Grp170 during ERAD and suggest that positioning this client-release factor at the retrotranslocation site may afford a mechanism to couple client release from BiP and retrotranslocation.
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48103 btsai@umich.edu inouet@umich.edu.
authors.forename: Takamasa
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48103 btsai@umich.edu inouet@umich.edu.
authors.forename: Billy
authors.initials: B
authors.lastname: Tsai
mesh_terms: D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D060746:Endoplasmic Reticulum-Associated Degradation; D006031:Glycosylation; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D011228:Prealbumin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D020662:Guanine Nucleotide Exchange Factors; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D011228:Prealbumin; C050087:oxygen-regulated proteins; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex