ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation.
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.
Kouroku
Y
Y
Division of Development, National Institute of Neuroscience, 4-1-1 Ogawahigashi-machi, Kodaira, Tokyo 187-8502, Japan.
Fujita
E
E
Tanida
I
I
Ueno
T
T
Isoai
A
A
Kumagai
H
H
Ogawa
S
S
Kaufman
R J
RJ
Kominami
E
E
Momoi
T
T
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D000071187:Autophagy-Related Protein 5; D053454:Caspase 12 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D010436:Pepstatins / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020836:Protein Structure, Quaternary / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000378:metabolism*
D000225:Adenine; D000071187:Autophagy-Related Protein 5; D053454:Caspase 12; D015852:Eukaryotic Initiation Factor-2; D007930:Leucine; D008869:Microtubule-Associated Proteins; D010436:Pepstatins; D010455:Peptides; D012333:RNA, Messenger; D020123:Sirolimus; D019892:eIF-2 Kinase; C495773:Atg5 protein, mouse; C480860:Map1lc3b protein, mouse; C097188:polyglutamine; C025946:3-methyladenine; C108192:aloxistatin; C031375:pepstatin