title: Homocysteine-induced endoplasmic reticulum protein (Herp) is up-regulated in sporadic inclusion-body myositis and in endoplasmic reticulum stress-induced cultured human muscle fibers.
abstract: Herp is a stress-response protein localized in the endoplasmic reticulum (ER) membrane. Herp was proposed to improve ER-folding, decrease ER protein load, and participate in ER-associated degradation (ERAD). Intra-muscle-fiber ubiquitinated multiprotein-aggregates containing, among other proteins, either amyloid-beta (Abeta) or phosphorylated tau are characteristic of sporadic inclusion-body myositis (s-IBM). ER stress and proteasome inhibition appear to play a role in s-IBM pathogenesis. We have now studied Herp in s-IBM muscle fibers and in ER-stress-induced or proteasome-inhibited cultured human muscle fibers. In s-IBM muscle fibers: (i) Herp was strongly immunoreactive in the form of aggregates, which co-localized with Abeta, GRP78, and beta2 proteasome subunit; (ii) Herp mRNA and protein were increased. In ER-stress-induced cultured human muscle fibers: (i) Herp immunoreactivity was diffusely increased; (ii) Herp mRNA and protein were increased. In proteasome-inhibited cultured human muscle fibers: (i) Herp immunoreactivity was in the form of aggregates; (ii) Herp protein was increased, but its mRNA was not. Accordingly, in s-IBM muscle fibers: (i) increase of Herp might be due to both ER-stress and proteasome inhibition; (ii) co-localization of Herp with Abeta, proteasome, and ER-chaperone GRP78 could reflect its possible role in processing and degradation of cytotoxic proteins in ER.
authors.affiliation: USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, California 90017-1912, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Nogalska
authors.forename: W King
authors.initials: WK
authors.lastname: Engel
authors.forename: Janis
authors.initials: J
authors.lastname: McFerrin
authors.forename: Koichi
authors.initials: K
authors.lastname: Kokame
authors.forename: Hiroto
authors.initials: H
authors.lastname: Komano
authors.forename: Valerie
authors.initials: V
authors.lastname: Askanas
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008565:Membrane Proteins / Q000378:metabolism*; D016253:Microscopy, Immunoelectron / Q000379:methods; D018832:Molecular Chaperones / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D025801:Ubiquitin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; C485932:HERPUD1 protein, human; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D025801:Ubiquitin; D006710:Homocysteine; D046988:Proteasome Endopeptidase Complex