An arsenite-inducible 19S regulatory particle-associated protein adapts proteasomes to proteotoxicity.
Protein misfolding caused by exposure to arsenite is associated with transcriptional activation of the AIRAP gene. We report here that AIRAP is an arsenite-inducible subunit of the proteasome's 19S cap that binds near PSMD2 at the 19S base. Compared to the wild-type, knockout mouse cells or C. elegans lacking AIRAP accumulate more polyubiquitylated proteins and exhibit higher levels of stress when exposed to arsenite, and proteasomes isolated from arsenite-treated AIRAP knockout cells are relatively impaired in substrate degradation in vitro. AIRAP's association with the 19S cap reverses the stabilizing affect of ATP on the 26S proteasome during particle purification, and AIRAP-containing proteasomes, though constituted of 19S and 20S subunits, acquire features of hybrid proteasomes with both 19S and 11S regulatory caps. These features include enhanced cleavage of peptide substrates and suggest that AIRAP adapts the cell's core protein degradation machinery to counteract proteotoxicity induced by an environmental toxin.
Stanhill
Ariel
A
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA.
Haynes
Cole M
CM
Zhang
Yuhong
Y
Min
Guangwei
G
Steele
Matthew C
MC
Kalinina
Juliya
J
Martinez
Enid
E
Pickart
Cecile M
CM
Kong
Xiang-Peng
XP
Ron
David
D
D000222:Adaptation, Physiological / Q000187:drug effects*; D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D018869:Heat-Shock Response; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism
D018053:Arsenites; D029742:Caenorhabditis elegans Proteins; D021122:Protein Subunits; D016601:RNA-Binding Proteins; D025801:Ubiquitin; C436043:Zfand2a protein, mouse; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C119011:26S proteasome non-ATPase regulatory subunit 13; C015001:arsenite