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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenine / analogs & derivatives
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Adenine / pharmacology
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Animals
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Autophagy* / drug effects
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Autophagy-Related Protein 5
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Caspase 12 / metabolism
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Cell Death / drug effects
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / enzymology
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Endoplasmic Reticulum / metabolism*
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Endoplasmic Reticulum / pathology
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Enzyme Activation / drug effects
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Eukaryotic Initiation Factor-2 / metabolism*
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Gene Expression Regulation / drug effects
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Leucine / analogs & derivatives
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Leucine / pharmacology
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Lysosomes / drug effects
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Lysosomes / enzymology
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Mice
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Microtubule-Associated Proteins / deficiency
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism*
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Models, Biological
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Pepstatins / pharmacology
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Peptides / chemistry
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Peptides / metabolism*
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Phosphorylation / drug effects
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Protein Structure, Quaternary / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Sirolimus / pharmacology
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eIF-2 Kinase / metabolism*
Substances
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Atg5 protein, mouse
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Autophagy-Related Protein 5
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Eukaryotic Initiation Factor-2
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Map1lc3b protein, mouse
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Microtubule-Associated Proteins
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Pepstatins
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Peptides
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RNA, Messenger
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polyglutamine
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3-methyladenine
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PERK kinase
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eIF-2 Kinase
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Caspase 12
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Leucine
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Adenine
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aloxistatin
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pepstatin
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Sirolimus