Whi2 is a conserved negative regulator of TORC1 in response to low amino acids

Xianghui Chen, Guiqin Wang, Yu Zhang, Margaret Dayhoff-Brannigan, Nicola L. Diny, Mingjun Zhao, Ge He, Cierra N. Sing, Kyle A. Metz, Zachary D. Stolp, Abdel Aouacheria, Wen Chih Cheng, J Marie Hardwick, Xinchen Teng

Research output: Contribution to journalArticle

Abstract

Yeast WHI2 was originally identified in a genetic screen for regulators of cell cycle arrest and later suggested to function in general stress responses. However, the function of Whi2 is unknown. Whi2 has predicted structure and sequence similarity to human KCTD family proteins, which have been implicated in several cancers and are causally associated with neurological disorders but are largely uncharacterized. The identification of conserved functions between these yeast and human proteins may provide insight into disease mechanisms. We report that yeast WHI2 is a new negative regulator of TORC1 required to suppress TORC1 activity and cell growth specifically in response to low amino acids. In contrast to current opinion, WHI2 is dispensable for TORC1 inhibition in low glucose. The only widely conserved mechanism that actively suppresses both yeast and mammalian TORC1 specifically in response to low amino acids is the conserved SEACIT/GATOR1 complex that inactivates the TORC1-activating RAG-like GTPases. Unexpectedly, Whi2 acts independently and simultaneously with these established GATOR1-like Npr2-Npr3-Iml1 and RAG-like Gtr1-Gtr2 complexes, and also acts independently of the PKA pathway. Instead, Whi2 inhibits TORC1 activity through its binding partners, protein phosphatases Psr1 and Psr2, which were previously thought to only regulate amino acid levels downstream of TORC1. Furthermore, the ability to suppress TORC1 is conserved in the SKP1/BTB/POZ domain-containing, Whi2-like human protein KCTD11 but not other KCTD family members tested.

Original languageEnglish (US)
Article numbere1007592
JournalPLoS Genetics
Volume14
Issue number8
DOIs
StatePublished - Aug 1 2018

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yeast
amino acid
yeasts
Amino Acids
amino acids
protein
proteins
nervous system diseases
Yeasts
guanosinetriphosphatase
phosphatase
cell growth
cancer
stress response
glucose
neoplasms
Aptitude
Fungal Proteins
mechanistic target of rapamycin complex 1
Phosphoprotein Phosphatases

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Chen, X., Wang, G., Zhang, Y., Dayhoff-Brannigan, M., Diny, N. L., Zhao, M., ... Teng, X. (2018). Whi2 is a conserved negative regulator of TORC1 in response to low amino acids. PLoS Genetics, 14(8), [e1007592]. https://doi.org/10.1371/journal.pgen.1007592

Whi2 is a conserved negative regulator of TORC1 in response to low amino acids. / Chen, Xianghui; Wang, Guiqin; Zhang, Yu; Dayhoff-Brannigan, Margaret; Diny, Nicola L.; Zhao, Mingjun; He, Ge; Sing, Cierra N.; Metz, Kyle A.; Stolp, Zachary D.; Aouacheria, Abdel; Cheng, Wen Chih; Hardwick, J Marie; Teng, Xinchen.

In: PLoS Genetics, Vol. 14, No. 8, e1007592, 01.08.2018.

Research output: Contribution to journalArticle

Chen, X, Wang, G, Zhang, Y, Dayhoff-Brannigan, M, Diny, NL, Zhao, M, He, G, Sing, CN, Metz, KA, Stolp, ZD, Aouacheria, A, Cheng, WC, Hardwick, JM & Teng, X 2018, 'Whi2 is a conserved negative regulator of TORC1 in response to low amino acids', PLoS Genetics, vol. 14, no. 8, e1007592. https://doi.org/10.1371/journal.pgen.1007592
Chen X, Wang G, Zhang Y, Dayhoff-Brannigan M, Diny NL, Zhao M et al. Whi2 is a conserved negative regulator of TORC1 in response to low amino acids. PLoS Genetics. 2018 Aug 1;14(8). e1007592. https://doi.org/10.1371/journal.pgen.1007592
Chen, Xianghui ; Wang, Guiqin ; Zhang, Yu ; Dayhoff-Brannigan, Margaret ; Diny, Nicola L. ; Zhao, Mingjun ; He, Ge ; Sing, Cierra N. ; Metz, Kyle A. ; Stolp, Zachary D. ; Aouacheria, Abdel ; Cheng, Wen Chih ; Hardwick, J Marie ; Teng, Xinchen. / Whi2 is a conserved negative regulator of TORC1 in response to low amino acids. In: PLoS Genetics. 2018 ; Vol. 14, No. 8.
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abstract = "Yeast WHI2 was originally identified in a genetic screen for regulators of cell cycle arrest and later suggested to function in general stress responses. However, the function of Whi2 is unknown. Whi2 has predicted structure and sequence similarity to human KCTD family proteins, which have been implicated in several cancers and are causally associated with neurological disorders but are largely uncharacterized. The identification of conserved functions between these yeast and human proteins may provide insight into disease mechanisms. We report that yeast WHI2 is a new negative regulator of TORC1 required to suppress TORC1 activity and cell growth specifically in response to low amino acids. In contrast to current opinion, WHI2 is dispensable for TORC1 inhibition in low glucose. The only widely conserved mechanism that actively suppresses both yeast and mammalian TORC1 specifically in response to low amino acids is the conserved SEACIT/GATOR1 complex that inactivates the TORC1-activating RAG-like GTPases. Unexpectedly, Whi2 acts independently and simultaneously with these established GATOR1-like Npr2-Npr3-Iml1 and RAG-like Gtr1-Gtr2 complexes, and also acts independently of the PKA pathway. Instead, Whi2 inhibits TORC1 activity through its binding partners, protein phosphatases Psr1 and Psr2, which were previously thought to only regulate amino acid levels downstream of TORC1. Furthermore, the ability to suppress TORC1 is conserved in the SKP1/BTB/POZ domain-containing, Whi2-like human protein KCTD11 but not other KCTD family members tested.",
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