RRC ID 34525
Author Sawamura N, Wakabayashi S, Matsumoto K, Yamada H, Asahi T.
Title Cereblon is recruited to aggresome and shows cytoprotective effect against ubiquitin-proteasome system dysfunction.
Journal Biochem. Biophys. Res. Commun.
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.
Volume 464(4)
Pages 1054-1059
Published 2015-9-4
DOI 10.1016/j.bbrc.2015.07.068
PII S0006-291X(15)30298-9
PMID 26188093
MeSH Animals Codon, Nonsense Cytoprotection / genetics Cytoprotection / physiology* Enzyme Inhibitors / pharmacology Gene Knockdown Techniques Humans Intellectual Disability / etiology Intellectual Disability / genetics Intellectual Disability / metabolism Intranuclear Inclusion Bodies / genetics Intranuclear Inclusion Bodies / metabolism Intranuclear Inclusion Bodies / pathology Microtubules / drug effects Microtubules / metabolism Nocodazole / pharmacology PC12 Cells Peptide Hydrolases / deficiency Peptide Hydrolases / genetics Peptide Hydrolases / metabolism* Proteasome Endopeptidase Complex / drug effects Proteasome Endopeptidase Complex / metabolism* Protein Aggregation, Pathological / genetics Protein Aggregation, Pathological / metabolism Protein Aggregation, Pathological / pathology RNA, Small Interfering / genetics Rats Recombinant Proteins / genetics Recombinant Proteins / metabolism Thalidomide / analogs & derivatives Thalidomide / pharmacology Ubiquitin / metabolism* Ubiquitin-Protein Ligases / antagonists & inhibitors Ubiquitin-Protein Ligases / metabolism
IF 2.559
Times Cited 5
WOS Category BIOPHYSICS BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
DNA material Genome Network Project Clone IRAL038I16 (HGY095408)