DAP1, a negative regulator of autophagy, controls SubAB-mediated apoptosis and autophagy.
Infect Immun
; 82(11): 4899-908, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-25183729
ABSTRACT
Autophagy and apoptosis play critical roles in cellular homeostasis and survival. Subtilase cytotoxin (SubAB), produced by non-O157 type Shiga-toxigenic Escherichia coli (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 c 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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Autofagia
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Subtilisinas
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Regulação da Expressão Gênica
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Apoptose
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Proteínas de Escherichia coli
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Proteínas Reguladoras de Apoptose
Limite:
Humans
Idioma:
En
Revista:
Infect Immun
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Japão