SUGT1

SUGT1 is a molecular chaperone that supports protein quality control and stability across multiple cellular processes, frequently acting in concert with HSP90 (PMID:42036143). In mitosis it is required for kinetochore assembly, ensuring correct localization of the kinetochore components Dsn1 and Hec1, and its loss impairs proliferation (PMID:32483152). SUGT1 also stabilizes microtubule plus-ends by modulating microtubule acetylation and promoting EB1 comet formation, a function exploited by HIV-1 for retrograde trafficking and nuclear import (PMID:32514048). A recurring theme is its chaperone activity toward leucine-rich repeat proteins: co-expression of SUGT1 markedly enhances the yield and quality of SHOC2 and the SHOC2-MRAS-PPP1CA holoenzyme (PMID:35131438). SUGT1 additionally engages the ubiquitin-proteasome system, interacting with the E3 ligase TRIM21 to promote p21 ubiquitination and thereby preventing G2/M arrest and senescence (PMID:39872547). Through a SUGT1/HSP90/NLRP3 complex it holds the NLRP3 inflammasome in an inactive resting state (PMID:42036143), and it lies upstream of the NLRP3/caspase-1/GSDMD pyroptosis axis (PMID:37317573). SUGT1 is also a target of pathogen effectors that hijack its function, as the C. parvum effector CpCML binds SUGT1 and drives its nuclear redistribution to reprogram PI3K/AKT-NF-κB signaling and impair autophagy (PMID:42119958).

1. 2020 Medium

   Establishing that SUGT1 controls microtubule plus-end dynamics defined a cytoskeletal function and revealed how a chaperone-associated factor can be co-opted for viral trafficking.

   Evidence siRNA knockdown with EB1 comet imaging, microtubule acetylation assays and HIV-1 permissiveness in lymphocytes and macrophages

   PMID:32514048

   Open questions at the time

   • Direct biochemical mechanism linking SUGT1 to EB1 or tubulin acetylation enzymes not defined
   • Whether the +MT role requires HSP90 not tested
2. 2020 Medium

   Demonstrating that SUGT1 is needed for correct loading of Dsn1 and Hec1 placed it as a required factor in kinetochore assembly during mitosis.

   Evidence Loss-of-function knockout/knockdown with immunofluorescence of kinetochore markers and in vivo muscle regeneration assays

   PMID:32483152

   Open questions at the time

   • Whether SUGT1 chaperones kinetochore subunits directly versus indirectly is unresolved
   • Molecular interaction with Dsn1/Hec1 not shown biochemically
3. 2022 Medium

   Reconstituting LRR protein expression with SUGT1 co-expression provided direct biochemical evidence for its chaperone activity toward leucine-rich repeat proteins.

   Evidence Polycistronic baculovirus expression of SHOC2 and the SHOC2-MRAS-PPP1CA complex with and without SUGT1, assessing yield and quality

   PMID:35131438

   Open questions at the time

   • Whether SUGT1 binds LRR clients directly in vivo not shown
   • Requirement for HSP90 in this chaperone activity not tested
4. 2023 Medium

   Identifying the SUGT1-TRIM21 interaction and p21 ubiquitination connected SUGT1 to ubiquitin-mediated proteostasis and cell-cycle/senescence control.

   Evidence Reciprocal co-immunoprecipitation, p21 ubiquitination assays and cell cycle analysis in muscle stem cells

   PMID:39872547

   Open questions at the time

   • Whether SUGT1 acts as a chaperone/adaptor for TRIM21 or modulates ligase activity is unclear
   • Direct SUGT1-p21 contact not demonstrated
5. 2023 Medium

   Placing SUGT1 downstream of miR-141-3p and upstream of NLRP3/caspase-1/GSDMD linked it to pyroptosis regulation.

   Evidence Dual luciferase 3'UTR reporter, SUGT1 overexpression rescue and pyroptosis marker quantification in colonic epithelial cells

   PMID:37317573

   Open questions at the time

   • Mechanism by which SUGT1 modulates NLRP3 in this context not resolved
   • Direct molecular interaction not established here
6. 2024 Low

   Showing ELF1 binds the SUGT1 promoter began to define transcriptional control of SUGT1 expression.

   Evidence Promoter analysis and chromatin immunoprecipitation in ovarian cancer cells

   PMID:39167956

   Open questions at the time

   • No functional mutagenesis of the ELF1 binding site reported
   • Physiological contexts of ELF1-driven SUGT1 expression unknown
7. 2025 Low

   Linking SUGT1 to FH degradation and PI3K/AKT signaling extended its proteasome-directed role to cancer cell proliferation and migration.

   Evidence siRNA knockdown, ubiquitin-proteasome pathway analysis and FH knockdown rescue in ovarian cancer cells

   PMID:40731365

   Open questions at the time

   • No direct ubiquitination reconstitution reported
   • Whether SUGT1 directly binds FH unknown
   • Single method set in one lab
8. 2025 Low

   A cell-model study positioned the HSP90/SUGT1 chaperone module within the Aβ/tau proteostasis network via GSK-3β.

   Evidence Cell model overexpression/knockdown with western blot for tau phosphorylation and Aβ42 quantification (preprint)

   PMID:bio_10.1101_2025.03.28.646065

   Open questions at the time

   • Preprint, single cell model, no mutagenesis or reconstitution
   • Direct client relationship not demonstrated
9. 2026 Medium

   Defining the SUGT1/HSP90/NLRP3 complex established a direct chaperone-based mechanism keeping the NLRP3 inflammasome inactive and identified SUGT1 as a druggable node.

   Evidence Immunoprecipitation of the SUGT1-HSP90-NLRP3 complex plus CETSA, SPR and dot blot for Notoginsenoside-Fa binding

   PMID:42036143

   Open questions at the time

   • Structural basis of NLRP3 stabilization not resolved
   • How activation releases NLRP3 from the complex not defined
10. 2026 Medium

    Discovering that the C. parvum effector CpCML binds SUGT1 and forces its nuclear relocation revealed pathogen hijacking of SUGT1 to reprogram PI3K/AKT-NF-κB signaling and autophagy.

    Evidence Biochemical binding assays, co-IP, subcellular fractionation, knockdown/overexpression and PI3K inhibitor epistasis

    PMID:42119958

    Open questions at the time

    • Endogenous nucleocytoplasmic shuttling determinants of SUGT1 not mapped
    • Whether nuclear SUGT1 retains chaperone function unknown

• How SUGT1's HSP90 co-chaperone activity is mechanistically partitioned across its diverse client repertoire—kinetochore subunits, microtubule regulators, LRR proteins, NLRP3, and ubiquitination substrates—remains unresolved.
• No structural model of SUGT1-client engagement
• Determinants of client selectivity unknown
• Distinction between direct chaperone and adaptor roles not established