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1.
iScience ; 25(2): 103675, 2022 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-35141499

RESUMO

Unsatisfied kinetochore-microtubule attachment activates the spindle assembly checkpoint to inhibit the metaphase-anaphase transition. However, some cells eventually override mitotic arrest by mitotic slippage. Here, we show that inactivation of TORC1 kinase elicits mitotic slippage in budding yeast and human cells. Yeast mitotic slippage was accompanied with aberrant aspects, such as degradation of the nucleolar protein Net1, release of phosphatase Cdc14, and anaphase-promoting complex/cyclosome (APC/C)-Cdh1-dependent degradation of securin and cyclin B in metaphase. This mitotic slippage caused chromosome instability. In human cells, mammalian TORC1 (mTORC1) inactivation also invoked mitotic slippage, indicating that TORC1 inactivation-induced mitotic slippage is conserved from yeast to mammalian cells. However, the invoked mitotic slippage in human cells was not dependent on APC/C-Cdh1. This study revealed an unexpected involvement of TORC1 in mitosis and provides information on undesirable side effects of the use of TORC1 inhibitors as immunosuppressants and anti-tumor drugs.

2.
J Mol Biol ; 434(2): 167360, 2022 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-34798133

RESUMO

Phosphatidylinositol 3-phosphate (PI3P), a scaffold of membrane-associated proteins required for diverse cellular events, is produced by Vps34-containing phosphatidylinositol 3-kinase (PI3K). PI3K complex I (PI3KCI)-generated PI3P is required for macroautophagy, whereas PI3K complex II (PI3KCII)-generated PI3P is required for endosomal sorting complex required for transport (ESCRT)-mediated multi-vesicular body (MVB) formation in late endosomes. ESCRT also promotes vacuolar membrane remodeling in microautophagy after nutrient starvation and inactivation of target of rapamycin complex 1 (TORC1) protein kinase in budding yeast. Whereas PI3KCI and macroautophagy are critical for the nutrient starvation response, the physiological roles of PI3KCII and microautophagy during starvation are largely unknown. Here, we showed that PI3KCII-produced PI3P on vacuolar membranes is required for microautophagy induction and survival in nutrient-stressed conditions. PI3KCII is required for Vps27 (an ESCRT-0 component) recruitment and ESCRT-0 complex formation on vacuolar surfaces after TORC1 inactivation. Forced recruitment of Vps27 onto vacuolar membranes rescued the defect in microautophagy induction in PI3KCII-deficient cells, indicating that a critical role of PI3P on microautophagy induction is Vps27 recruitment onto vacuolar surfaces. Finally, vacuolar membrane-associated Vps27 was able to recover survival during nutrient starvation in cells lacking PI3KCII or Vps27. This study revealed that the PI3KCII-PI3P-Vps27 axis on vacuolar membranes is critical for ESCRT-mediated microautophagy induction and nutrient stress adaptation.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Microautofagia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Vacúolos/metabolismo , Membranas Intracelulares/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas de Membrana/metabolismo , Nutrientes , Fosfatos de Fosfatidilinositol , Transporte Proteico , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição
3.
Cell Signal ; 62: 109344, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31201849

RESUMO

Target of rapamycin complex 1 (TORC1) protein kinase responds to various stresses including genotoxic stress. However, its molecular mechanism is poorly understood. Here, we show that DNA damage induces nonselective and selective autophagy in budding yeast. DNA damage caused the attenuation of TORC1 activity, dephosphorylation of Atg13, and autophagy induction. The TORC1-upstream Rag GTPase Gtr1 was not required for TORC1 inactivation and autophagy induction after DNA damage. Furthermore, DNA damage responsive protein kinases Mec1/ATM and Tel1/ATR, and stress-responsive mitogen-activated protein kinase Mpk1/Slt2 were required for the full induction of autophagy. Autophagic proteolysis was required for DNA damage tolerance in TORC1 inactive conditions. This study revealed that multiple protein kinases regulate DNA damage-induced autophagy.


Assuntos
Autofagia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Relacionadas à Autofagia/genética , Dano ao DNA/genética , Regulação da Expressão Gênica no Desenvolvimento , Regulação Fúngica da Expressão Gênica/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Saccharomyces cerevisiae/genética , Transdução de Sinais/genética
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