Human-IAPP disrupts the autophagy/lysosomal pathway in pancreatic Β-cells

Protective role of p62-positive cytoplasmic inclusions

J. F. Rivera, T. Gurlo, M. Daval, C. J. Huang, Aleksey V Matveyenko, P. C. Butler, S. Costes

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

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-dependant 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.

Original languageEnglish (US)
Pages (from-to)415-426
Number of pages12
JournalCell Death and Differentiation
Volume18
Issue number3
DOIs
StatePublished - Mar 2011
Externally publishedYes

Fingerprint

Islet Amyloid Polypeptide
Inclusion Bodies
Autophagy
Apoptosis
Poisons
Amyloidogenic Proteins
Intracellular Membranes
Lysosomes
Hyperglycemia
Type 2 Diabetes Mellitus
Proteolysis
Proteins
Obesity
Insulin

Keywords

  • autophagy
  • islet amyloid polypeptide
  • p62/sequestosome 1
  • pancreatic b-cell
  • type II diabetes mellitus

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Human-IAPP disrupts the autophagy/lysosomal pathway in pancreatic Β-cells : Protective role of p62-positive cytoplasmic inclusions. / Rivera, J. F.; Gurlo, T.; Daval, M.; Huang, C. J.; Matveyenko, Aleksey V; Butler, P. C.; Costes, S.

In: Cell Death and Differentiation, Vol. 18, No. 3, 03.2011, p. 415-426.

Research output: Contribution to journalArticle

Rivera, J. F. ; Gurlo, T. ; Daval, M. ; Huang, C. J. ; Matveyenko, Aleksey V ; Butler, P. C. ; Costes, S. / Human-IAPP disrupts the autophagy/lysosomal pathway in pancreatic Β-cells : Protective role of p62-positive cytoplasmic inclusions. In: Cell Death and Differentiation. 2011 ; Vol. 18, No. 3. pp. 415-426.
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