title: Unfolded protein response-induced ERdj3 secretion links ER stress to extracellular proteostasis.
abstract: The Unfolded Protein Response (UPR) indirectly regulates extracellular proteostasis through transcriptional remodeling of endoplasmic reticulum (ER) proteostasis pathways. This remodeling attenuates secretion of misfolded, aggregation-prone proteins during ER stress. Through these activities, the UPR has a critical role in preventing the extracellular protein aggregation associated with numerous human diseases. Here, we demonstrate that UPR activation also directly influences extracellular proteostasis through the upregulation and secretion of the ER HSP40 ERdj3/DNAJB11. Secreted ERdj3 binds misfolded proteins in the extracellular space, substoichiometrically inhibits protein aggregation, and attenuates proteotoxicity of disease-associated toxic prion protein. Moreover, ERdj3 can co-secrete with destabilized, aggregation-prone proteins in a stable complex under conditions where ER chaperoning capacity is overwhelmed, preemptively providing extracellular chaperoning of proteotoxic misfolded proteins that evade ER quality control. This regulated co-secretion of ERdj3 with misfolded clients directly links ER and extracellular proteostasis during conditions of ER stress. ERdj3 is, to our knowledge, the first metazoan chaperone whose secretion into the extracellular space is regulated by the UPR, revealing a new mechanism by which UPR activation regulates extracellular proteostasis.
authors.affiliation: Department of Molecular & Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Genereux
authors.affiliation: Department of Molecular & Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Qu
authors.affiliation: Department of Infectious Diseases, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Minghai
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Molecular & Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ryno
authors.affiliation: Degenerative Disease Research Program, Sanford Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Shoulders
authors.affiliation: Degenerative Disease Research Program, Sanford Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.affiliation: Department of Infectious Diseases, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Corinne I
authors.initials: CI
authors.lastname: Lasmézas
authors.affiliation: Department of Molecular & Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.affiliation: Department of Molecular & Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA wiseman@scripps.edu.
authors.forename: R Luke
authors.initials: RL
authors.lastname: Wiseman
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D059865:Endoplasmic Reticulum Stress; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056811:Unfolded Protein Response
chemical_list: C494648:DNAJB11 protein, human; D050956:HSP40 Heat-Shock Proteins; D011328:Prions; D066329:Protein Aggregates
keywords: ER stress; ERdj3; extracellular proteostasis; molecular chaperones; unfolded protein response