Affinage

SZT2

KICSTOR complex protein SZT2 · UniProt Q5T011

Length
3432 aa
Mass
378.0 kDa
Annotated
2026-06-10
28 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SZT2 is a large scaffolding protein that organizes the amino acid-sensing branch of mTORC1 signaling by assembling a SZT2-orchestrated GATOR (SOG) complex, simultaneously recruiting GATOR1 and GATOR2 to lysosomes through synergistic interactions that are required for the lysosomal localization of GATOR components (PMID:28199315). Loss of SZT2 produces constitutive mTORC1 signaling even under nutrient-deprived conditions, and this hyperactivation can be corrected by restoring downstream nutrient-sensing components such as DEPDC5, lysosome-targeted WDR59, or lysosome-targeted SESN2, placing SZT2 upstream of GATOR1/2 and SESN (PMID:28199315). In human cells, biallelic SZT2 loss-of-function leads to constitutive lysosomal mTOR localization and elevated S6K/S6 phosphorylation under amino acid starvation, with exaggerated responses to slight amino acid stimulation (PMID:31430354), and cell-based functional assays have validated specific pathogenic variants and reclassified variants of uncertain significance in this pathway (PMID:35773235). The consequences of this regulatory role are evident across cell types: SZT2 sustains hematopoietic stem cell homeostasis and self-renewal, acting synergistically with the growth-factor-sensing arm (TSC1) such that combined loss drives a ~10-fold increase in mTORC1 activity, ~100-fold increase in ROS, and rapid stem cell depletion (PMID:36250465), and in human brain organoids SZT2 mutation elevates mTORC1 activity in the SVZ and expands outer radial glia and upper-layer neurons, linking SZT2 dysregulation to cortical over-expansion (PMID:41535455). SZT2 was originally identified as a brain-enriched, evolutionarily conserved protein whose mutation confers a low seizure threshold in mice (PMID:19624305). Beyond its core mTORC1 role, interactome analysis has linked SZT2 to autophagy regulation and ciliogenesis (PMID:34685691).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2009 Medium

    Before any biochemical role was known, forward genetics established SZT2 as a brain-enriched, conserved protein whose disruption alters neuronal excitability, framing it as a developmentally important gene.

    Evidence Chemical mutagenesis screen and gene-trap alleles in mice with genetic mapping and RT-PCR validation

    PMID:19624305

    Open questions at the time
    • No molecular mechanism or biochemical activity established
    • No protein interaction partners identified
    • Link to mTORC1 not yet known
  2. 2017 High

    The central question of what SZT2 does molecularly was answered by showing it scaffolds GATOR1 and GATOR2 into a lysosomal SOG complex, defining SZT2 as the upstream organizer of amino acid-sensing input to mTORC1.

    Evidence Reciprocal co-IP, lysosome fractionation, genetic epistasis rescue with GATOR/SESN components, and mouse knockout with fasting-resistant mTORC1 activity

    PMID:28199315

    Open questions at the time
    • No high-resolution structure of the SOG complex
    • Stoichiometry and assembly order of SZT2-GATOR1-GATOR2 not resolved
    • Mechanism of nutrient signal transduction through the scaffold unclear
  3. 2018 Low

    A first hint that SZT2 loss has consequences beyond mTOR signaling came from a metabolic readout, raising the possibility of a mitochondrial energy role.

    Evidence Metabolic profiling / mitochondrial energy metabolism assays in patient-derived cells

    PMID:30564332

    Open questions at the time
    • Single patient case without detailed methods or controls
    • Causal link between SZT2 and mitochondrial metabolism not established
    • Not independently replicated
  4. 2019 Medium

    The mouse and cell-line mechanism was confirmed to operate in human disease by demonstrating constitutive lysosomal mTOR and elevated S6K/S6 phosphorylation in patient-derived cells carrying biallelic SZT2 mutations.

    Evidence Phospho-immunoblotting and immunofluorescence for lysosomal mTOR in patient LCLs under starvation and stimulation

    PMID:31430354

    Open questions at the time
    • Single-lab patient-derived cell study
    • Does not resolve which protein interactions are disrupted by specific mutations
    • Does not connect cellular phenotype to organismal disease features
  5. 2021 Medium

    Unbiased interactome mapping extended SZT2's reach beyond GATOR/KICSTOR, implicating it in autophagy and ciliogenesis while confirming nutrient-independent mTORC1 control in knockout cells.

    Evidence AP-MS interactome under catabolic/anabolic conditions plus mTORC1 and autophagy marker immunoblotting and ciliogenesis assays in KO cells

    PMID:34685691

    Open questions at the time
    • Ciliogenesis effect described as preliminary
    • Functional significance of non-GATOR interactors not validated
    • Single lab
  6. 2022 Medium

    Cell-based functional assays operationalized the mechanism for clinical genetics, identifying loss-of-function variants (including an Ashkenazi Jewish founder allele) and reclassifying variants of uncertain significance.

    Evidence Phospho-S6K readout in SZT2-null cells re-expressing variants, with haplotype analysis; complemented by in silico structural modeling of a GATOR1-binding residue

    PMID:35352205 PMID:35773235

    Open questions at the time
    • Structural prediction of Ser1170 GATOR1 binding not experimentally validated
    • Variant assay reflects S6K readout only, not full pathway
    • Genotype-phenotype correlation across variants incomplete
  7. 2022 High

    Tissue-specific genetics revealed that SZT2 nutrient sensing is functionally critical in stem cells and acts synergistically with the growth-factor arm, defining how two mTORC1 inputs integrate physiologically.

    Evidence HSC-specific conditional knockout with bone marrow repopulation assays, SZT2/TSC1 double-KO epistasis, phospho-S6K/S6 immunoblotting, and ROS measurement

    PMID:36250465

    Open questions at the time
    • Molecular basis of synergy with TSC1 not defined biochemically
    • Source of the dramatic ROS elevation not mechanistically dissected
    • Generalizability beyond HSCs unaddressed
  8. 2026 Medium

    Human brain organoids connected SZT2-driven mTORC1 dysregulation to a specific neurodevelopmental phenotype, linking progenitor mTORC1 hyperactivity to outer radial glia expansion and cortical over-growth.

    Evidence iPSC-derived brain organoids from SZT2 patient lines with oRGC marker immunostaining and mTORC1 activity readouts in SVZ-like regions

    PMID:41535455

    Open questions at the time
    • Single-lab organoid model
    • Causal chain from mTORC1 to oRGC expansion not fully dissected
    • Relationship to human macrocephaly remains inferential

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SZT2 transduces nutrient signals through the SOG scaffold at atomic resolution, and whether its autophagy, ciliogenesis, and mitochondrial links are direct or downstream of mTORC1, remain unresolved.
  • No experimental structure of SZT2 or the SOG complex
  • Direct versus indirect basis of non-mTOR functions unknown
  • Mechanism coupling amino acid status to GATOR1/2 regulation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005764 lysosome 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-9612973 Autophagy 1
Partners
DEPDC5SESN2WDR59
Complex memberships
KICSTORSZT2-orchestrated GATOR (SOG) complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 SZT2 recruits a fraction of GATOR1 and GATOR2 to form a SZT2-orchestrated GATOR (SOG) complex; the SZT2-GATOR1 and SZT2-GATOR2 interactions are synergistic, and an intact SOG complex is required for lysosomal localization of GATOR components. SZT2 deficiency results in constitutive mTORC1 signaling under nutrient-deprived conditions. Hyperactivation of mTORC1 in SZT2-deficient cells was partially corrected by overexpression of DEPDC5, lysosome-targeted WDR59, or lysosome-targeted SESN2, placing SZT2 upstream of GATOR1/2 and SESN in nutrient sensing. Co-immunoprecipitation, lysosome fractionation, genetic rescue (overexpression of GATOR1/GATOR2/SESN2 components), mouse knockout (neonatal lethality with failure to inactivate mTORC1 during fasting), cell-based mTORC1 activity assays Nature High 28199315
2009 Szt2 is a large (~378 kDa) protein encoded by a 72-exon gene with no significant sequence similarity to other proteins; a splice-donor mutation after exon 32 causes transcriptional read-through and premature stop, conferring low seizure threshold in mice. A gene-trap mutation in exon 21 also conferred low seizure threshold and some embryonic lethality in homozygotes, indicating a developmental role. Szt2 is highly expressed in brain and is evolutionarily conserved across land vertebrates and many invertebrates. Chemical mutagenesis screen, genetic mapping, RT-PCR (splice mutation verification), gene-trap allele phenotypic analysis Genes, brain, and behavior Medium 19624305
2019 Patient-derived lymphoblastoid cell lines (LCLs) carrying biallelic SZT2 loss-of-function mutations show increased phosphorylation of S6K and S6 under amino acid starvation, and constitutive lysosomal localization of mTOR, demonstrating that SZT2 mutations cause hyperactivation of mTORC1 in human cells. Patients' LCLs also display excessive mTORC1 response to slight amino acid stimulation. Phospho-immunoblotting (pS6K, pS6), immunofluorescence for lysosomal mTOR localization in patient-derived LCLs under amino acid starvation and stimulation conditions PloS one Medium 31430354
2022 SZT2 is required for hematopoietic stem cell (HSC) homeostasis through nutrient-mediated mTORC1 regulation. HSC-specific SZT2 ablation decreased the HSC reserve and impaired repopulating capacity. Simultaneous ablation of SZT2 and TSC1 produced a synergistic (~10-fold) increase in mTORC1 activity and ~100-fold increase in ROS production, rapidly depleting HSCs, causing pancytopenia and premature mouse death, demonstrating that nutrient-sensing (SZT2) and growth-factor-sensing (TSC1) arms of mTORC1 regulation act synergistically in stem cells. Conditional HSC-specific knockout mice, bone marrow transplantation (repopulating capacity assay), phospho-S6K/S6 immunoblotting, ROS measurement, double-knockout epistasis analysis The Journal of clinical investigation High 36250465
2022 A functional mTORC1 assay identified SZT2 p.Val1984del as a loss-of-function variant; haplotype analysis revealed it is a founder variant in individuals of Ashkenazi Jewish ancestry. The assay platform was used to reclassify variants of uncertain significance in SZT2, confirming the protein's role in the amino acid-sensing arm of mTORC1 signaling. Cell-based mTORC1 signaling functional assay (phospho-S6K readout in SZT2-null cells re-expressing variants), haplotype analysis Brain : a journal of neurology Medium 35773235
2021 Systematic interactome analysis of SZT2 identified interaction partners beyond known GATOR/KICSTOR components, including proteins related to autophagy, ciliogenesis regulation, neurogenesis, and neurodegenerative processes. SZT2 KO cells showed increased mTORC1 signaling (reversible by Rapamycin or Torin) and elevated autophagic component levels independent of nutrient conditions. Preliminary data indicated SZT2 alters ciliogenesis. Affinity purification/mass spectrometry interactome analysis under catabolic and anabolic conditions, SZT2 KO cell lines with mTORC1 and autophagy marker immunoblotting, ciliogenesis assay Cells Medium 34685691
2018 Patient-derived compound heterozygous Szt2 variants impair mitochondrial energy metabolism, providing the first evidence of a metabolic consequence of SZT2 loss of function beyond mTOR signaling. Metabolic profiling / mitochondrial energy metabolism assays in patient-derived cells Clinical case reports Low 30564332
2026 In human brain organoids derived from SZT2 mutant iPSCs, there is a significantly greater number of outer radial glial cells (oRGCs) in the SVZ-like layer and more upper-layer neurons compared to controls. SZT2 mutant organoids show higher mTORC1 activity in the SVZ, suggesting SZT2 dysfunction causes cortical expansion (and potentially macrocephaly) through mTORC1 dysregulation in neural stem/progenitor cells. iPSC-derived brain organoids from SZT2 patient lines, immunostaining for oRGC markers, mTORC1 activity readouts in SVZ-like regions Scientific reports Medium 41535455
2022 Crystal structure simulation analysis of SZT2 missense variant c.3508A>G/p.Ser1170Gly predicted impaired binding of SZT2 to GATOR1, suggesting the Ser1170 residue is important for SZT2–GATOR1 interaction and that disruption leads to mTORC1 overactivation. In silico crystal structure simulation/molecular modeling of SZT2 missense variants Neurological sciences Low 35352205

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 SZT2 dictates GATOR control of mTORC1 signalling. Nature 159 28199315
2013 Biallelic SZT2 mutations cause infantile encephalopathy with epilepsy and dysmorphic corpus callosum. American journal of human genetics 68 23932106
2009 Szt2, a novel gene for seizure threshold in mice. Genes, brain, and behavior 49 19624305
2016 Early-life epileptic encephalopathy secondary to SZT2 pathogenic recessive variants. Epileptic disorders : international epilepsy journal with videotape 27 27248490
2017 Novel biallelic SZT2 mutations in 3 cases of early-onset epileptic encephalopathy. Clinical genetics 24 28556953
2018 Mutations in SZT2 result in early-onset epileptic encephalopathy and leukoencephalopathy. American journal of medical genetics. Part A 17 29696782
2020 Developmental and epileptic encephalopathy due to SZT2 genomic variants: Emerging features of a syndromic condition. Epilepsy & behavior : E&B 16 32402703
2018 A novel homozygous mutation in SZT2 gene in Saudi family with developmental delay, macrocephaly and epilepsy. Genes & genomics 15 30315519
2023 SZT2 variants associated with partial epilepsy or epileptic encephalopathy and the genotype-phenotype correlation. Frontiers in molecular neuroscience 14 37213690
2018 Compound heterozygous SZT2 mutations in two siblings with early-onset epilepsy, intellectual disability and macrocephaly. Seizure 14 30818181
2019 Constitutive activation of mTORC1 signaling induced by biallelic loss-of-function mutations in SZT2 underlies a discernible neurodevelopmental disease. PloS one 13 31430354
2019 Novel SZT2 mutations in three patients with developmental and epileptic encephalopathies. Molecular genetics & genomic medicine 12 31397114
2018 SZT2 mutation in a boy with intellectual disability, seizures and autistic features. European journal of medical genetics 11 30359774
2018 Novel metabolic signatures of compound heterozygous Szt2 variants in a case of early-onset of epileptic encephalopathy. Clinical case reports 11 30564332
2022 SZT2 maintains hematopoietic stem cell homeostasis via nutrient-mediated mTORC1 regulation. The Journal of clinical investigation 10 36250465
2018 Identification of a rare homozygous SZT2 variant due to uniparental disomy in a patient with a neurodevelopmental disorder. Intractable & rare diseases research 10 30560016
2024 A novel hypoxia-induced lncRNA, SZT2-AS1, boosts HCC progression by mediating HIF heterodimerization and histone trimethylation under a hypoxic microenvironment. Cell death and differentiation 9 39572656
2022 mTORC1 functional assay reveals SZT2 loss-of-function variants and a founder in-frame deletion. Brain : a journal of neurology 9 35773235
2021 The SZT2 Interactome Unravels New Functions of the KICSTOR Complex. Cells 9 34685691
2021 A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant. Epilepsia open 6 33681650
2020 Biallelic SZT2 variants in a child with developmental and epileptic encephalopathy. Epileptic disorders : international epilepsy journal with videotape 4 32723703
2023 Insight into Genetic Mutations of SZT2: Is It a Syndrome? Biomedicines 3 37760843
2022 Induced Pluripotent Stem Cell (iPSC) Lines from a Family with Resistant Epileptic Encephalopathy Caused by Compound Heterozygous Mutations in SZT2 Gene. International journal of molecular sciences 3 36361881
2022 Genetic analysis of developmental and epileptic encephalopathy caused by novel biallelic SZT2 gene mutations in three Chinese Han infants: a case series and literature review. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2 35352205
2025 Novel SZT2::MAST2 Fusion Detected in Salivary Duct Carcinoma. Case reports in pathology 1 41357819
2023 Clinical phenotype and genetic characteristics of SZT2 related diseases: A case report and literature review. Seizure 1 38134649
2021 The Dysfunctional Gangway: SZT2-associated Epilepsy with Thick Corpus Callosum. Journal of pediatric neurosciences 1 36531768
2026 Brain organoid models of SZT2-related disease reveal an overproduction of outer radial glial cells through mTORC1 activation. Scientific reports 0 41535455

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