ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation

Cell Death Differ. 2007 Feb;14(2):230-9. doi: 10.1038/sj.cdd.4401984. Epub 2006 Jun 23.

Abstract

Expanded polyglutamine 72 repeat (polyQ72) aggregates induce endoplasmic reticulum (ER) stress-mediated cell death with caspase-12 activation and vesicular formation (autophagy). We examined this relationship and the molecular mechanism of autophagy formation. Rapamycin, a stimulator of autophagy, inhibited the polyQ72-induced cell death with caspase-12 activation. PolyQ72, but not polyQ11, stimulated Atg5-Atg12-Atg16 complex-dependent microtubule-associated protein 1 (MAP1) light chain 3 (LC3) conversion from LC3-I to -II, which plays a key role in autophagy. The eucaryotic translation initiation factor 2 alpha (eIF2alpha) A/A mutation, a knock-in to replace a phosphorylatable Ser51 with Ala51, and dominant-negative PERK inhibited polyQ72-induced LC3 conversion. PolyQ72 as well as ER stress stimulators upregulated Atg12 mRNA and proteins via eIF2alpha phosphorylation. Furthermore, Atg5 deficiency as well as the eIF2alpha A/A mutation increased the number of cells showing polyQ72 aggregates and polyQ72-induced caspase-12 activation. Thus, autophagy formation is a cellular defense mechanism against polyQ72-induced ER-stress-mediated cell death by degrading polyQ72 aggregates, with PERK/eIF2alpha phosphorylation being involved in polyQ72-induced LC3 conversion.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Autophagy* / drug effects
  • Autophagy-Related Protein 5
  • Caspase 12 / metabolism
  • Cell Death / drug effects
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / enzymology
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / pathology
  • Enzyme Activation / drug effects
  • Eukaryotic Initiation Factor-2 / metabolism*
  • Gene Expression Regulation / drug effects
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Lysosomes / drug effects
  • Lysosomes / enzymology
  • Mice
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism*
  • Models, Biological
  • Pepstatins / pharmacology
  • Peptides / chemistry
  • Peptides / metabolism*
  • Phosphorylation / drug effects
  • Protein Structure, Quaternary / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sirolimus / pharmacology
  • eIF-2 Kinase / metabolism*

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Eukaryotic Initiation Factor-2
  • MAP1LC3 protein, mouse
  • Microtubule-Associated Proteins
  • Pepstatins
  • Peptides
  • RNA, Messenger
  • polyglutamine
  • 3-methyladenine
  • PERK kinase
  • eIF-2 Kinase
  • Caspase 12
  • Leucine
  • Adenine
  • aloxistatin
  • pepstatin
  • Sirolimus