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Bioorthogonal Chemical Imaging of Cell Metabolism Regulated by Aromatic Amino Acids
Published on: May 12, 2023
Whi2 is a conserved negative regulator of TORC1 in response to low amino acids
Xianghui Chen1, Guiqin Wang1, Yu Zhang1
1Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
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.
Insights
Yeast WHI2 protein suppresses TORC1 activity and cell growth during low amino acid conditions. This function is conserved in human KCTD11, offering insights into neurological disorders and cancer.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Yeast WHI2 was initially identified as a cell cycle regulator and later implicated in stress responses, but its precise function remained unclear.
- WHI2 shares structural and sequence similarities with human KCTD proteins, which are linked to cancers and neurological disorders.
- Understanding conserved functions between yeast and human proteins can illuminate disease mechanisms.
Purpose of the Study:
- To elucidate the unknown function of yeast WHI2.
- To investigate the role of WHI2 in regulating the Target of Rapamycin Complex 1 (TORC1) pathway.
- To explore the conserved function of WHI2-like proteins in human diseases.
Main Methods:
- Genetic screening in yeast to identify regulators of cell cycle arrest and stress responses.
- Analysis of WHI2's role in TORC1 signaling under nutrient-limiting conditions (low amino acids and glucose).
- Comparative analysis of WHI2 function with human KCTD family proteins, including KCTD11.
Main Results:
- Yeast WHI2 acts as a novel negative regulator of TORC1, specifically suppressing TORC1 activity and cell growth in response to low amino acids.
- WHI2 is not required for TORC1 inhibition under low glucose conditions, contrary to previous assumptions.
- WHI2 functions independently of the established SEACIT/GATOR1 complex and the PKA pathway, but acts through protein phosphatases Psr1 and Psr2.
- The TORC1-suppressing function of WHI2 is conserved in the human protein KCTD11.
Conclusions:
- Yeast WHI2 is a crucial negative regulator of TORC1 under amino acid starvation, operating independently of known pathways.
- The discovery of WHI2's role and its conservation in KCTD11 provides a new avenue for understanding TORC1 regulation and related human diseases.
- WHI2's interaction with Psr1 and Psr2 reveals a novel mechanism for nutrient-sensing downstream of TORC1.
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