Abstract
Protein synthesis regulation via mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has key roles in neural development and function, and its dysregulation is involved in neurodevelopmental disorders associated with autism and intellectual disability. mTOR regulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3 complex and by controlling phosphorylation of key translational regulators. Collybistin (CB), a neuron-specific Rho-GEF responsible for X-linked intellectual disability with epilepsy, also interacts with eIF3, and its binding partner gephyrin associates with mTOR. Therefore, we hypothesized that CB also binds mTOR and affects mTORC1 signaling activity in neuronal cells. Here, by using induced pluripotent stem cell-derived neural progenitor cells from a male patient with a deletion of entire CB gene and from control individuals, as well as a heterologous expression system, we describe that CB physically interacts with mTOR and inhibits mTORC1 signaling pathway and protein synthesis. These findings suggest that disinhibited mTORC1 signaling may also contribute to the pathological process in patients with loss-of-function variants in CB.
Publication types
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Case Reports
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Autistic Disorder / genetics*
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Autistic Disorder / metabolism
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Autistic Disorder / physiopathology
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Case-Control Studies
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Eukaryotic Initiation Factor-3 / genetics*
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Eukaryotic Initiation Factor-3 / metabolism
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Gene Deletion*
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Gene Expression Regulation
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Genetic Vectors / chemistry
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Genetic Vectors / metabolism
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HEK293 Cells
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Humans
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Induced Pluripotent Stem Cells / metabolism
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Induced Pluripotent Stem Cells / pathology
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Intellectual Disability / genetics*
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Intellectual Disability / metabolism
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Intellectual Disability / physiopathology
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Male
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Mechanistic Target of Rapamycin Complex 1
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Multiprotein Complexes / genetics*
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Multiprotein Complexes / metabolism
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Neural Stem Cells / metabolism
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Neural Stem Cells / pathology
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Peptide Chain Initiation, Translational
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Primary Cell Culture
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Protein Binding
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Rho Guanine Nucleotide Exchange Factors / deficiency
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Rho Guanine Nucleotide Exchange Factors / genetics*
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Signal Transduction
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TOR Serine-Threonine Kinases / genetics*
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TOR Serine-Threonine Kinases / metabolism
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Transfection
Substances
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ARHGEF9 protein, human
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Eukaryotic Initiation Factor-3
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Multiprotein Complexes
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Rho Guanine Nucleotide Exchange Factors
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MTOR protein, human
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases