title: UCHL1 deficiency exacerbates human islet amyloid polypeptide toxicity in β-cells: evidence of interplay between the ubiquitin/proteasome system and autophagy.
abstract: The islet in type 2 diabetes mellitus (T2DM) is characterized by a deficit in β-cells and increased β-cell apoptosis attributable at least in part to intracellular toxic oligomers of IAPP (islet amyloid polypeptide). β-cells of individuals with T2DM are also characterized by accumulation of polyubiquitinated proteins and deficiency in the deubiquitinating enzyme UCHL1 (ubiquitin carboxyl-terminal esterase L1 [ubiquitin thiolesterase]), accounting for a dysfunctional ubiquitin/proteasome system. In the present study, we used mouse genetics to elucidate in vivo whether a partial deficit in UCHL1 enhances the vulnerability of β-cells to human-IAPP (hIAPP) toxicity, and thus accelerates diabetes onset. We further investigated whether a genetically induced deficit in UCHL1 function in β-cells exacerbates hIAPP-induced alteration of the autophagy pathway in vivo. We report that a deficit in UCHL1 accelerated the onset of diabetes in hIAPP transgenic mice, due to a decrease in β-cell mass caused by increased β-cell apoptosis. We report that UCHL1 dysfunction aggravated the hIAPP-induced defect in the autophagy/lysosomal pathway, illustrated by the marked accumulation of autophagosomes and cytoplasmic inclusions positive for SQSTM1/p62 and polyubiquitinated proteins with lysine 63-specific ubiquitin chains. Collectively, this study shows that defective UCHL1 function may be an early contributor to vulnerability of pancreatic β-cells for protein misfolding and proteotoxicity, hallmark defects in islets of T2DM. Also, given that deficiency in UCHL1 exacerbated the defective autophagy/lysosomal degradation characteristic of hIAPP proteotoxicity, we demonstrate a previously unrecognized role of UCHL1 in the function of the autophagy/lysosomal pathway in β-cells.
authors.affiliation: Larry L. Hillblom Islet Research Center; David Geffen School of Medicine; University of California, Los Angeles; Los Angeles, CA USA.
authors.forename: Safia
authors.initials: S
authors.lastname: Costes
authors.affiliation: Larry L. Hillblom Islet Research Center; David Geffen School of Medicine; University of California, Los Angeles; Los Angeles, CA USA.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Gurlo
authors.affiliation: Larry L. Hillblom Islet Research Center; David Geffen School of Medicine; University of California, Los Angeles; Los Angeles, CA USA.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Rivera
authors.affiliation: Larry L. Hillblom Islet Research Center; David Geffen School of Medicine; University of California, Los Angeles; Los Angeles, CA USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Butler
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D058228:Islet Amyloid Polypeptide / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D058228:Islet Amyloid Polypeptide; D050505:Mutant Proteins; D046988:Proteasome Endopeptidase Complex; D011994:Recombinant Proteins; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse
keywords: SQSTM1/p62; apoptosis; autophagy; diabetes; islet amyloid polypeptide; ubiquitin carboxyl-terminal esterase L1; β-cell