The UBL domain of PLIC-1 regulates aggresome formation.
Defects in protein folding and the proteasomal pathway have been linked with many neurodegenerative diseases. PLIC-1 (protein linking IAP to the cytoskeleton) is a ubiquitin-like protein that binds to the ubiquitin-interacting motif (UIM) of the proteasomal subunit S5a. Here, we show that PLIC-1 also binds to the UIM proteins ataxin 3--a deubiquitinating enzyme--HSJ1a--a co-chaperone--and EPS15 (epidermal growth factor substrate 15)--an endocytic protein. Using a polyglutamine (polyQ) disease model, we found that both endogenous PLIC-1 and EPS15 localize to perinuclear aggresomes, and that polyQ enhances their in vivo interaction. We show that knockdown of PLIC-1 and EPS15 by RNA interference reduces aggresome formation. In addition, PLIC-1(DeltaUBL) functions as a dominant-negative mutant, blocking both polyQ transport to aggresomes and the association of EPS15 with dispersed aggregates. We also show that PLIC-1 is upregulated by arsenite-induced protein misfolding. These results indicate a role for PLIC-1 in the protein aggregation-stress pathway, and we propose a novel function for the ubiquitin-like (UBL) domain--by means of UBL-UIM interactions--in transport to aggresomes.
Heir
Renu
R
Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montreal, Quebec H3A2B2, Canada.
Ablasou
Celine
C
Dumontier
Emilie
E
Elliott
Meghan
M
Fagotto-Kaufmann
Christine
C
Bedford
Fiona K
FK
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D000071183:Autophagy-Related Proteins; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D008957:Models, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D014162:Transfection; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C486204:EPN2 protein, human; C107792:UBQLN1 protein, human; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex