Affinage

SZT2

KICSTOR complex protein SZT2 · UniProt Q5T011

Length
3432 aa
Mass
378.0 kDa
Annotated
2026-04-28
28 papers in source corpus 7 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SZT2 is a large scaffolding protein that orchestrates amino acid sensing upstream of mTORC1 by assembling GATOR1, GATOR2, and SESN proteins into a lysosome-associated SOG (SZT2-orchestrated GATOR) complex, thereby enabling nutrient-dependent mTORC1 inactivation (PMID:28199315). Loss of SZT2 causes constitutive mTORC1 hyperactivation under nutrient deprivation, leading to impaired hematopoietic stem cell homeostasis with depleted HSC reserves and synergistic ROS elevation when combined with TSC1 loss (PMID:36250465), and to excess outer radial glia production and cortical expansion in human brain organoids (PMID:41535455). Biallelic loss-of-function mutations in SZT2, including a recurrent founder variant in Ashkenazi Jewish individuals, cause early-onset epileptic encephalopathy with macrocephaly (PMID:35773235, PMID:31430354).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2017 High

    Establishing how SZT2 connects to mTORC1 signaling resolved the question of its molecular function: SZT2 nucleates a SOG complex by synergistically binding GATOR1 and GATOR2, recruiting them to the lysosome where they mediate SESN-dependent nutrient sensing and mTORC1 inhibition upon amino acid deprivation.

    Evidence Co-immunoprecipitation, lysosomal fractionation, genetic rescue (DEPDC5 overexpression, lysosome-targeted WDR59/SESN2), and neonatal-lethal mouse KO

    PMID:28199315

    Open questions at the time
    • Structural basis for SZT2's synergistic bridging of GATOR1 and GATOR2 is unknown
    • Whether SZT2 directly binds RAG GTPases or solely acts through GATOR/SESN remains unresolved
    • Lysosomal targeting determinants within SZT2 are not mapped
  2. 2018 Low

    A case linking SZT2 variants to mitochondrial energy defects raised the question of whether SZT2 has mTORC1-independent roles in mitochondrial metabolism.

    Evidence Single patient case study with metabolic/mitochondrial functional analyses in patient cells

    PMID:30564332

    Open questions at the time
    • Single patient without independent replication or mechanistic dissection of how SZT2 affects mitochondria
    • Whether the mitochondrial phenotype is secondary to chronic mTORC1 hyperactivation is untested
    • No mitochondrial interaction partners of SZT2 are identified
  3. 2019 Medium

    Validation in human patient-derived cells confirmed that biallelic SZT2 loss-of-function mutations produce constitutive mTORC1 activity and mTOR mis-localization to lysosomes during amino acid starvation, translating the mouse findings to human disease.

    Evidence Patient-derived lymphoblastoid cell lines with phosphorylation assays (S6K, S6) and immunofluorescence for lysosomal mTOR

    PMID:31430354

    Open questions at the time
    • Only lymphoblastoid cells examined; neuronal cell types not tested
    • Downstream consequences of constitutive mTORC1 in patient cells (e.g., autophagy, protein synthesis) not characterized
  4. 2021 Medium

    Systematic interactome mapping expanded the SZT2 interaction network beyond GATOR to include autophagy receptors and ciliogenesis regulators, and showed that SZT2 KO elevates autophagic components irrespective of metabolic state.

    Evidence Mass spectrometry-based interactome under catabolic and anabolic conditions; SZT2 KO cell lines with Rapamycin/Torin rescue

    PMID:34685691

    Open questions at the time
    • Direct physical interactions with autophagy receptors and ciliogenesis regulators await reciprocal validation
    • Whether autophagy dysregulation is mTORC1-dependent or an independent SZT2 function is not resolved
    • Functional relevance of ciliogenesis interactors remains untested
  5. 2022 High

    Demonstrating that SZT2 loss depletes HSCs and synergizes with TSC1 loss to massively elevate mTORC1 and ROS established SZT2 as operating in a nutrient-sensing axis parallel to TSC for stem cell maintenance.

    Evidence HSC-specific conditional KO mice, bone marrow transplantation, genetic epistasis with TSC1 double KO, ROS quantification

    PMID:36250465

    Open questions at the time
    • Whether mTORC1-independent mechanisms contribute to HSC depletion is unknown
    • ROS source (mitochondrial vs. other) upon SZT2/TSC1 double loss is not identified
    • Whether rapamycin rescues the HSC phenotype in vivo was not reported
  6. 2022 Medium

    Functional classification of a recurrent SZT2 founder variant (p.Val1984del) as loss-of-function in the mTORC1 pathway provided a direct genotype-to-mechanism link for clinical variant interpretation.

    Evidence Cell-based mTORC1 functional assay for SZT2 variants, haplotype analysis in Ashkenazi Jewish cohort

    PMID:35773235

    Open questions at the time
    • Structural consequence of Val1984 deletion on SOG complex assembly is not characterized
    • Functional assay validated for limited number of variants
  7. 2026 Medium

    Brain organoid modeling revealed that SZT2 dysfunction drives overproduction of outer radial glia through elevated SVZ mTORC1, providing a cellular mechanism for the macrocephaly seen in patients.

    Evidence Patient-derived iPSC brain organoids with immunostaining for oRGC/neuron markers and regional mTORC1 activity measurement

    PMID:41535455

    Open questions at the time
    • Whether mTORC1 inhibition rescues the oRGC phenotype in organoids was not shown
    • In vivo validation in animal models of cortical expansion is lacking
    • Cell-type-specific SZT2 expression in developing human cortex is not characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural architecture of SZT2, its precise lysosomal targeting mechanism, and whether it has mTORC1-independent functions in autophagy, ciliogenesis, or mitochondrial metabolism remain open questions.
  • No structural or cryo-EM model of SZT2 or the SOG complex exists
  • mTORC1-independent roles suggested by interactome data are functionally unvalidated
  • Tissue-specific requirements for SZT2 beyond brain and hematopoietic system are unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005764 lysosome 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 1
Partners
DEPDC5SESN2TSC1WDR59
Complex memberships
SOG (SZT2-orchestrated GATOR) complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 SZT2 recruits a fraction of mammalian GATOR1 and GATOR2 to form a SZT2-orchestrated GATOR (SOG) complex; the interaction of SZT2 with GATOR1 and GATOR2 is synergistic, and an intact SOG complex is required for lysosomal localization of the complex and GATOR/SESN-dependent nutrient sensing and mTORC1 regulation. Co-immunoprecipitation, lysosomal fractionation, genetic rescue experiments (DEPDC5 overexpression, lysosome-targeted WDR59/SESN2), mouse knockout model with neonatal lethality phenotype Nature High 28199315
2017 SZT2 deficiency results in constitutive mTORC1 signalling under nutrient-deprived conditions in cells, and failure to inactivate mTORC1 during fasting in vivo, demonstrating SZT2 is required for mTORC1 downregulation upon nutrient deprivation. Mouse knockout (neonatal lethality), cell-based mTORC1 activity assays under nutrient deprivation, genetic rescue with DEPDC5/GATOR2 components Nature High 28199315
2019 Biallelic loss-of-function SZT2 mutations in patient-derived lymphoblastoid cell lines cause constitutive hyperactivation of mTORC1 (increased S6K and S6 phosphorylation) under amino acid starvation, and constitutive lysosomal localization of mTOR, confirming the loss-of-function mechanism in human patient cells. Patient-derived lymphoblastoid cell lines, phosphorylation assays (S6K, S6), immunofluorescence for lysosomal mTOR localization under amino acid starvation PloS one Medium 31430354
2021 Systematic interactome analysis of SZT2 identified interaction partners including mTORC1 and AMPK signaling components, autophagy regulators (selective autophagy receptors), ciliogenesis regulators, and neurogenesis-related proteins; SZT2 KO cells show increased mTORC1 signaling (reversible by Rapamycin/Torin) and elevated autophagic components independent of physiological conditions. Mass spectrometry-based interactome analysis under catabolic and anabolic conditions, SZT2 KO cell lines with mTORC1 activity measurement, Rapamycin/Torin pharmacological rescue Cells Medium 34685691
2022 SZT2 is required for hematopoietic stem cell (HSC) homeostasis via nutrient-mediated mTORC1 regulation; loss of SZT2 decreases HSC reserve and impairs repopulating capacity, and combined loss of SZT2 and TSC1 produces a synergistic ~10-fold increase in mTORC1 activity and ~100-fold increase in ROS, rapidly depleting HSCs. HSC-specific conditional KO mice, bone marrow transplantation repopulation assay, mTORC1 activity measurement, ROS quantification, double KO (SZT2 + TSC1) genetic epistasis The Journal of clinical investigation High 36250465
2022 A recurrent in-frame deletion SZT2 p.Val1984del is a loss-of-function variant in the mTORC1 signaling pathway, identified as a founder variant in individuals of Ashkenazi Jewish ancestry, using a functional mTORC1 assay to reclassify variants of uncertain significance. Cell-based mTORC1 functional assay for SZT2 variants, haplotype analysis for founder effect determination Brain : a journal of neurology Medium 35773235
2026 SZT2 dysfunction in human brain organoids causes overproduction of outer radial glial cells (oRGCs) in the SVZ-like layer and increased upper-layer neurons, through elevated mTORC1 activity in the SVZ, suggesting SZT2-mediated mTORC1 regulation controls cortical expansion and underlies macrocephaly. Patient-derived iPSC brain organoids, immunostaining for oRGC and neuron markers, mTORC1 activity measurement in SVZ region of organoids Scientific reports Medium 41535455
2018 SZT2 variants in a patient with early-onset epileptic encephalopathy impair mitochondrial energy metabolism, providing evidence for a pathogenic molecular mechanism involving mitochondrial dysfunction. Case study with metabolic/mitochondrial functional analyses in patient cells Clinical case reports Low 30564332

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 158 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
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
2025 Novel SZT2::MAST2 Fusion Detected in Salivary Duct Carcinoma. Case reports in pathology 0 41357819