title: Deletion of Herp facilitates degradation of cytosolic proteins.
abstract: Although intracellular stresses are believed to be involved in the process of neurodegeneration, it is not fully understood how one stress/stress response affects another. Herp is an endoplasmic reticulum (ER)-located membrane protein proposed to function in ER-associated degradation (ERAD). Herp is strongly induced by ER stress but rapidly degraded by proteasome. To elucidate the effect of Herp expression on proteolytic stress caused by impairment of the ubiquitin-proteasome system (UPS), we utilized 293T Herp knockdown (KD) cells and F9 Herp knockout cells. Knockdown of Herp gene unexpectedly facilitated the degradation of Parkinson's disease-associated cytosolic proteins such as alpha-synuclein and its binding partner, synphilin-1, and improved cell viability during proteasomal inhibition. A similar tendency was observed in F9 Herp knockout cells transfected with synphilin-1. Herp temporarily bound to alpha-synuclein, synphilin-1 and the E3 ligase SIAH1a during proteolytic stress but not during ER stress. Furthermore, deletion of Herp enhanced the amount of ubiquitinated protein in the cytosol during proteasomal inhibition, although it did not affect the activity or expression of proteasome. These results suggest that ERAD molecule Herp may delay the degradation of cytosolic proteins at the ubiquitination step.
authors.affiliation: Department of Neuroanatomy, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.
authors.forename: Hikari
authors.initials: H
authors.lastname: Miura
authors.forename: Koji
authors.initials: K
authors.lastname: Hashida
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Sudo
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Awa
authors.forename: Mika
authors.initials: M
authors.lastname: Takarada-Iemata
authors.forename: Koichi
authors.initials: K
authors.lastname: Kokame
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takahashi
authors.forename: Masayasu
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kitao
authors.forename: Osamu
authors.initials: O
authors.lastname: Hori
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D003600:Cytosol / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
chemical_list: D002352:Carrier Proteins; C485932:HERPUD1 protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C118958:SNCAIP protein, human; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D046988:Proteasome Endopeptidase Complex