The inositol 1,4,5-trisphosphate receptor regulates autophagy through its interaction with Beclin 1.
Cell Death Differ
; 16(7): 1006-17, 2009 Jul.
Article
em En
| MEDLINE
| ID: mdl-19325567
ABSTRACT
The inositol 1,4,5-trisphosphate receptor (IP(3)R) is a major regulator of apoptotic signaling. Through interactions with members of the Bcl-2 family of proteins, it drives calcium (Ca(2+)) transients from the endoplasmic reticulum (ER) to mitochondria, thereby establishing a functional and physical link between these organelles. Importantly, the IP(3)R also regulates autophagy, and in particular, its inhibition/depletion strongly induces macroautophagy. Here, we show that the IP(3)R antagonist xestospongin B induces autophagy by disrupting a molecular complex formed by the IP(3)R and Beclin 1, an interaction that is increased or inhibited by overexpression or knockdown of Bcl-2, respectively. An effect of Beclin 1 on Ca(2+) homeostasis was discarded as siRNA-mediated knockdown of Beclin 1 did not affect cytosolic or luminal ER Ca(2+) levels. Xestospongin B- or starvation-induced autophagy was inhibited by overexpression of the IP(3)R ligand-binding domain, which coimmunoprecipitated with Beclin 1. These results identify IP(3)R as a new regulator of the Beclin 1 complex that may bridge signals converging on the ER and initial phagophore formation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Autofagia
/
Proteínas Proto-Oncogênicas c-bcl-2
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Proteínas Reguladoras de Apoptose
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Receptores de Inositol 1,4,5-Trifosfato
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Proteínas de Membrana
/
Proteínas Associadas aos Microtúbulos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article