title: Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism.
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.
authors.affiliation: Hospital Israelita Albert Einstein, Instituto de Ensino e Pesquisa, São Paulo, Brazil.
authors.forename: Camila Oliveira Freitas
authors.initials: CO
authors.lastname: Machado
authors.affiliation: Hospital Israelita Albert Einstein, Instituto de Ensino e Pesquisa, São Paulo, Brazil.|Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Karina
authors.initials: K
authors.lastname: Griesi-Oliveira
authors.affiliation: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Carla
authors.initials: C
authors.lastname: Rosenberg
authors.affiliation: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.|Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Fernando
authors.initials: F
authors.lastname: Kok
authors.affiliation: Hospital Israelita Albert Einstein, Instituto de Ensino e Pesquisa, São Paulo, Brazil.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Martins
authors.affiliation: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Passos-Bueno
authors.affiliation: Hospital Israelita Albert Einstein, Instituto de Ensino e Pesquisa, São Paulo, Brazil.
authors.forename: Andrea Laurato
authors.initials: AL
authors.lastname: Sertie
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016022:Case-Control Studies; D039621:Eukaryotic Initiation Factor-3 / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D010442:Peptide Chain Initiation, Translational; D061251:Primary Cell Culture; D011485:Protein Binding; D064067:Rho Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: C577410:ARHGEF9 protein, human; D039621:Eukaryotic Initiation Factor-3; D046912:Multiprotein Complexes; D064067:Rho Guanine Nucleotide Exchange Factors; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases