Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Cell Rep ; 29(6): 1399-1409.e5, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31693882

RESUMO

Autophagy is stimulated by stress conditions and needs to be precisely tuned to ensure cellular homeostasis and organismal development and health. The kinase mechanistic target of rapamycin (mTOR) forms the enzymatic core of the highly conserved mTOR complexes mTORC1 and mTORC2. mTORC1 is a key inhibitor of autophagy, yet the function of mTORC2 in autophagy is controversial. We here show that inactivation of mTORC2 and its direct target serum- and glucocorticoid-inducible kinase 1 (SGK-1) potently induces autophagy and the autophagic degradation of mitochondria in C. elegans. Enhanced autophagy in mTORC2- or SGK-1-deficient animals contributes to their developmental and reproductive defects and is independent of the canonical SGK-1 effector DAF-16/FOXO. Importantly, we find that inactivation of mTORC2-SGK-1 signaling impairs mitochondrial homeostasis and triggers an increased release of mitochondria-derived reactive oxygen species (mtROS) to induce autophagy. Thus, mitochondrial stress couples reduced mTORC2 activity to enhanced autophagic turnover.


Assuntos
Caenorhabditis elegans/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Mitocôndrias/metabolismo , Mitofagia/genética , Animais , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , Proteína Companheira de mTOR Insensível à Rapamicina/genética , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/genética
2.
J Cell Biol ; 218(9): 3019-3038, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31431476

RESUMO

Retromer is an evolutionarily conserved multiprotein complex that orchestrates the endocytic recycling of integral membrane proteins. Here, we demonstrate that retromer is also required to maintain lysosomal amino acid signaling through mTORC1 across species. Without retromer, amino acids no longer stimulate mTORC1 translocation to the lysosomal membrane, which leads to a loss of mTORC1 activity and increased induction of autophagy. Mechanistically, we show that its effect on mTORC1 activity is not linked to retromer's role in the recycling of transmembrane proteins. Instead, retromer cooperates with the RAB7-GAP TBC1D5 to restrict late endosomal RAB7 into microdomains that are spatially separated from the amino acid-sensing domains. Upon loss of retromer, RAB7 expands into the ragulator-decorated amino acid-sensing domains and interferes with RAG-GTPase and mTORC1 recruitment. Depletion of retromer in Caenorhabditis elegans reduces mTORC1 signaling and extends the lifespan of the worms, confirming an evolutionarily conserved and unexpected role for retromer in the regulation of mTORC1 activity and longevity.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Longevidade , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Microdomínios da Membrana/metabolismo , Transdução de Sinais , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Microdomínios da Membrana/genética , Proteínas rab de Ligação ao GTP/genética , proteínas de unión al GTP Rab7
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...