| First Author | Costes S | Year | 2014 |
| Journal | Autophagy | Volume | 10 |
| Issue | 6 | Pages | 1004-14 |
| PubMed ID | 24879150 | Mgi Jnum | J:321046 |
| Mgi Id | MGI:6759166 | Doi | 10.4161/auto.28478 |
| Citation | Costes S, et al. (2014) UCHL1 deficiency exacerbates human islet amyloid polypeptide toxicity in beta-cells: evidence of interplay between the ubiquitin/proteasome system and autophagy. Autophagy 10(6):1004-14 |
| abstractText | The islet in type 2 diabetes mellitus (T2DM) is characterized by a deficit in beta-cells and increased beta-cell apoptosis attributable at least in part to intracellular toxic oligomers of IAPP (islet amyloid polypeptide). beta-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 beta-cells to human-IAPP (hIAPP) toxicity, and thus accelerates diabetes onset. We further investigated whether a genetically induced deficit in UCHL1 function in beta-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 beta-cell mass caused by increased beta-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 beta-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 beta-cells. |
