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, Guoqing; Sing, Cierra N.; Metz, Kyle; Stolp, Zachary D.; Aouacheria, Abdel; Cheng, Wenli; Hardwick, J. Marie; Teng, Xinchen

doi:10.1371/journal.pgen.1007592

Cited by 40 publications

(69 citation statements)

References 83 publications

(143 reference statements)

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“…A recent study showed that yeast Whi2 sharing a BTB domain homologous to that of human KCTD proteins is capable of inhibiting TORC1 under low amino acid conditions . Remarkably, human KCTD11 but not other KCTD proteins tested (KCTD7, KCTD8, KCTD11, KCTD12, and KCTD16) could suppress TORC1 activity when expressed in whi2 ‐deficient yeast and in mammalian cell lines under low amino acid conditions . Furthermore, knockdown of KCTD11 in HEK293 cells confirmed that KCTD11 is required to suppress mTORC1 during amino acid deprivation .…”

Section: Relevance Of Other Kctd Family Members To the Nervous Systemmentioning

confidence: 92%

“…Remarkably, human KCTD11 but not other KCTD proteins tested (KCTD7, KCTD8, KCTD11, KCTD12, and KCTD16) could suppress TORC1 activity when expressed in whi2 ‐deficient yeast and in mammalian cell lines under low amino acid conditions . Furthermore, knockdown of KCTD11 in HEK293 cells confirmed that KCTD11 is required to suppress mTORC1 during amino acid deprivation . The detailed molecular mechanism of how KCTD11 regulates mTORC1 activity is still unknown.…”

Section: Relevance Of Other Kctd Family Members To the Nervous Systemmentioning

confidence: 97%

“…Yeast WHI2 was later rediscovered for similar reasons, because spontaneous WHI2 mutations caused cells to continue growing inappropriately after switching cells to medium with low levels of amino acids . This is because Whi2 is required to suppress TORC1 kinase, the master regulator of cellular responses to nutrient status . Interestingly, knockdown of Kctd13 in neuro2A cells was reported to increase cell proliferation .…”

Section: Kctd Genes Associated With Neurodevelopmental and Neuropsychmentioning

confidence: 99%

“…NCBI recently revised the annotation of human KCTD11 as a 271 amino acid protein including a full BTB domain (KCTD11l, NP_001350571). A recent study showed that yeast Whi2 sharing a BTB domain homologous to that of human KCTD proteins is capable of inhibiting TORC1 under low amino acid conditions . Remarkably, human KCTD11 but not other KCTD proteins tested (KCTD7, KCTD8, KCTD11, KCTD12, and KCTD16) could suppress TORC1 activity when expressed in whi2 ‐deficient yeast and in mammalian cell lines under low amino acid conditions .…”

Section: Relevance Of Other Kctd Family Members To the Nervous Systemmentioning

confidence: 99%

“…However, new evidence supports roles for KCTDs in signaling pathways to indirectly modulate potassium channel activity. KCTDs appear to be involved in other processes, including nutrient sensing and autophagy, based on work in yeast showing that the yeast KCTD‐like protein Whi2 interacts with yeast phosphatases Psr1/Psr2 to regulate TORC1 activity . The plethora of effects of KCTD family proteins may reflect an adaptor function of KCTDs that recruits substrates for ubiquitination by cullin‐3 and subsequent degradation, though evidence also supports additional mechanisms.…”

Section: Perspectivesmentioning

confidence: 99%

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KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

et al. 2019

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The underlying molecular basis for neurodevelopmental or neuropsychiatric disorders is not known. In contrast, mechanistic understanding of other brain disorders including neurodegeneration has advanced considerably. Yet, these do not approach the knowledge accrued for many cancers with precision therapeutics acting on well‐characterized targets. Although the identification of genes responsible for neurodevelopmental and neuropsychiatric disorders remains a major obstacle, the few causally associated genes are ripe for discovery by focusing efforts to dissect their mechanisms. Here, we make a case for delving into mechanisms of the poorly characterized human KCTD gene family. Varying levels of evidence support their roles in neurocognitive disorders ( KCTD3 ), neurodevelopmental disease ( KCTD7 ), bipolar disorder ( KCTD12 ), autism and schizophrenia ( KCTD13 ), movement disorders ( KCTD17 ), cancer ( KCTD11 ), and obesity ( KCTD15 ). Collective knowledge about these genes adds enhanced value, and critical insights into potential disease mechanisms have come from unexpected sources. Translation of basic research on the KCTD‐related yeast protein Whi2 has revealed roles in nutrient signaling to mTORC1 (KCTD11) and an autophagy‐lysosome pathway affecting mitochondria (KCTD7). Recent biochemical and structure‐based studies (KCTD12, KCTD13, KCTD16) reveal mechanisms of regulating membrane channel activities through modulation of distinct GTPases. We explore how these seemingly varied functions may be disease related.

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Section: Relevance Of Other Kctd Family Members To the Nervous Systemmentioning

confidence: 92%

Section: Relevance Of Other Kctd Family Members To the Nervous Systemmentioning

confidence: 97%

Section: Kctd Genes Associated With Neurodevelopmental and Neuropsychmentioning

confidence: 99%

Section: Relevance Of Other Kctd Family Members To the Nervous Systemmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

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KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

et al. 2019

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KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy‐lysosome defect

Metz

Teng

Coppens

et al. 2018

Annals of Neurology

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Objective Several small case series identified KCTD7 mutations in patients with a rare autosomal recessive disorder designated progressive myoclonic epilepsy (EPM3) and neuronal ceroid lipofuscinosis (CLN14). Despite the name KCTD (potassium channel tetramerization domain), KCTD protein family members lack predicted channel domains. We sought to translate insight gained from yeast studies to uncover disease mechanisms associated with deficiencies in KCTD7 of unknown function. Methods Novel KCTD7 variants in new and published patients were assessed for disease causality using genetic analyses, cell-based functional assays of patient fibroblasts and knockout yeast, and electron microscopy of patient samples. Results Patients with KCTD7 mutations can exhibit movement disorders or developmental regression before seizure onset, and are distinguished from similar disorders by an earlier age of onset. Although most published KCTD7 patient variants were excluded from a genome sequence database of normal human variations, most newly identified patient variants are present in this database, potentially challenging disease causality. However, genetic analysis and impaired biochemical interactions with cullin 3 support a causal role for patient KCTD7 variants, suggesting deleterious alleles of KCTD7 and other rare disease variants may be underestimated. Both patient-derived fibroblasts and yeast lacking Whi2 with sequence similarity to KCTD7 have impaired autophagy consistent with brain pathology. Interpretation Bi-allelic KCTD7 mutations define a neurodegenerative disorder with lipofuscin and lipid droplet accumulation but without defining features of neuronal ceroid lipofuscinosis or lysosomal storage disorders. KCTD7 deficiency appears to cause an underlying autophagy-lysosome defect conserved in yeast, thereby assigning a biological role for KCTD7.

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Downregulation of miR‐337‐3p in hypoxia/reoxygenation neuroblastoma cells increases KCTD11 expression

Zhu,

Xin,

et al. 2024

J Biochem & Molecular Tox

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Neurodegeneration is linked to the progressive loss of neural function and is associated with several diseases. Hypoxia is a hallmark in many of these diseases, and several therapies have been developed to treat this disease, including gene expression therapies that should be tightly controlled to avoid side effects. Cells experiencing hypoxia undergo a series of physiological responses that are induced by the activation of various transcription factors. Modulation of microRNA (miRNA) expression to alter transcriptional regulation has been demonstrated to be beneficial in treating multiple diseases, and in this study, we therefore explored potential miRNA candidates that could influence hypoxia‐induced nerve cell death. Our data suggest that in mouse neuroblasts Neuro‐2a cells with hypoxia/reoxygenation (H/R), miR‐337‐3p is downregulated to increase the expression of Potassium channel tetramerization domain containing 11 (KCTD11) and subsequently promote apoptosis. Here, we demonstrate for the first time that KCTD11 plays a role in the cellular response to hypoxia, and we also provide a possible regulatory mechanism by identifying the axis of miR‐337‐3p/KCTD11 as a promising candidate modulator of nerve cell survival after H/R exposure.

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

Cited by 40 publications

References 83 publications

KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders

KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy‐lysosome defect

Downregulation of miR‐337‐3p in hypoxia/reoxygenation neuroblastoma cells increases KCTD11 expression

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