Human-IAPP disrupts the autophagy/lysosomal pathway in pancreatic β-cells: protective role of p62-positive cytoplasmic inclusions.
In type II diabetes (T2DM), there is a deficit in β-cells, increased β-cell apoptosis and formation of intracellular membrane-permeant oligomers of islet amyloid polypeptide (IAPP). Human-IAPP (h-IAPP) is an amyloidogenic protein co-expressed with insulin by β-cells. IAPP expression is increased with obesity, the major risk factor for T2DM. In this study we report that increased expression of human-IAPP led to impaired autophagy, due at least in part to the disruption of lysosome-dependent degradation. This action of IAPP to alter lysosomal clearance in vivo depends on its propensity to form toxic oligomers and is independent of the confounding effect of hyperglycemia. We report that the scaffold protein p62 that delivers polyubiquitinated proteins to autophagy may have a protective role against human-IAPP-induced apoptosis, apparently by sequestrating protein targets for degradation. Finally, we found that inhibition of lysosomal degradation increases vulnerability of β-cells to h-IAPP-induced toxicity and, conversely, stimulation of autophagy protects β-cells from h-IAPP-induced apoptosis. Collectively, these data imply an important role for the p62/autophagy/lysosomal degradation system in protection against toxic oligomer-induced apoptosis.
Rivera
J F
JF
Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-7073, USA.
Gurlo
T
T
Daval
M
M
Huang
C J
CJ
Matveyenko
A V
AV
Butler
P C
PC
Costes
S
S
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002479:Inclusion Bodies / Q000187:drug effects / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009765:Obesity / Q000150:complications / Q000378:metabolism / Q000473:pathology; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D020011:Protective Agents / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D020836:Protein Structure, Quaternary; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D058228:Islet Amyloid Polypeptide; D020011:Protective Agents; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C491079:Sqstm1 protein, rat; D020123:Sirolimus
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