DAP1, a Negative Regulator of Autophagy, Controls SubAB-Mediated Apoptosis and Autophagy
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- Kinnosuke Yahiro
- Department of Molecular Infectiology, Graduate School of Medicine, Chiba University, Chiba, Japan
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- Hiroyasu Tsutsuki
- Department of Molecular Infectiology, Graduate School of Medicine, Chiba University, Chiba, Japan
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- Kohei Ogura
- Department of Molecular Infectiology, Graduate School of Medicine, Chiba University, Chiba, Japan
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- Sayaka Nagasawa
- Department of Molecular Infectiology, Graduate School of Medicine, Chiba University, Chiba, Japan
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- Joel Moss
- Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
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- Masatoshi Noda
- Department of Molecular Infectiology, Graduate School of Medicine, Chiba University, Chiba, Japan
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- B. A. McCormick
- editor
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説明
<jats:title>ABSTRACT</jats:title> <jats:p> Autophagy and apoptosis play critical roles in cellular homeostasis and survival. Subtilase cytotoxin (SubAB), produced by non-O157 type Shiga-toxigenic <jats:named-content content-type="genus-species">Escherichia coli</jats:named-content> (STEC), is an important virulence factor in disease. SubAB, a protease, cleaves a specific site on the endoplasmic reticulum (ER) chaperone protein BiP/GRP78, leading to ER stress, and induces apoptosis. Here we report that in HeLa cells, activation of a PERK (RNA-dependent protein kinase [PKR]-like ER kinase)-eIF2α (α subunit of eukaryotic initiation factor 2)-dependent pathway by SubAB-mediated BiP cleavage negatively regulates autophagy and induces apoptosis through death-associated protein 1 (DAP1). We found that SubAB treatment decreased the amounts of autophagy markers LC3-II and p62 as well as those of mTOR (mammalian target of rapamycin) signaling proteins ULK1 and S6K. These proteins showed increased expression levels in PERK knockdown or DAP1 knockdown cells. In addition, depletion of DAP1 in HeLa cells dramatically inhibited the SubAB-stimulated apoptotic pathway: SubAB-induced Bax/Bak conformational changes, Bax/Bak oligomerization, cytochrome <jats:italic>c</jats:italic> release, activation of caspases, and poly(ADP-ribose) polymerase (PARP) cleavage. These results show that DAP1 is a key regulator, through PERK-eIF2α-dependent pathways, of the induction of apoptosis and reduction of autophagy by SubAB. </jats:p>
収録刊行物
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- Infection and Immunity
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Infection and Immunity 82 (11), 4899-4908, 2014-11
American Society for Microbiology