title: Cereblon is recruited to aggresome and shows cytoprotective effect against ubiquitin-proteasome system dysfunction.
abstract: Cereblon (CRBN) is encoded by a candidate gene for autosomal recessive nonsyndromic intellectual disability (ID). The nonsense mutation, R419X, causes deletion of 24 amino acids at the C-terminus of CRBN, leading to mild ID. Although abnormal CRBN function may be associated with ID disease onset, its cellular mechanism is still unclear. Here, we examine the role of CRBN in aggresome formation and cytoprotection. In the presence of a proteasome inhibitor, exogenous CRBN formed perinuclear inclusions and co-localized with aggresome markers. Endogenous CRBN also formed perinuclear inclusions under the same condition. Treatment with a microtubule destabilizer or an inhibitor of the E3 ubiquitin ligase activity of CRBN blocked formation of CRBN inclusions. Biochemical analysis showed CRBN containing inclusions were high-molecular weight, ubiquitin-positive. CRBN overexpression in cultured cells suppressed cell death induced by proteasome inhibitor. Furthermore, knockdown of endogenous CRBN in cultured cells increased cell death induced by proteasome inhibitor, compared with control cells. Our results show CRBN is recruited to aggresome and has functional roles in cytoprotection against ubiquitin-proteasome system impaired condition.
authors.affiliation: Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan; Research Organization for Nano-life Innovation, Waseda University, Japan. Electronic address: naoya.sawamura@gmail.com.
authors.forename: Naoya
authors.initials: N
authors.lastname: Sawamura
authors.affiliation: Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Wakabayashi
authors.affiliation: Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan.
authors.forename: Kodai
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Yamada
authors.affiliation: Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan; Research Organization for Nano-life Innovation, Waseda University, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Asahi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018389:Codon, Nonsense; D019610:Cytoprotection / Q000235:genetics / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D008607:Intellectual Disability / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D045586:Intranuclear Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D015739:Nocodazole / Q000494:pharmacology; D016716:PC12 Cells; D010447:Peptide Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; D018389:Codon, Nonsense; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D025801:Ubiquitin; D013792:Thalidomide; C467566:pomalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D015739:Nocodazole
keywords: Aggresome; Cereblon; Cytoprotection; Intellectual disability; Ubiquitin-proteasome system