Affinage

TSG101

Tumor susceptibility gene 101 protein · UniProt Q99816

Length
390 aa
Mass
43.9 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TSG101 is the ubiquitin/peptide-cargo-recognition subunit of the ESCRT-I machinery that drives multivesicular body (MVB) biogenesis, receptor downregulation, and membrane scission (PMID:11208108, PMID:16707569). Its catalytically inactive ubiquitin E2 variant (UEV) domain — structurally an E2-fold lacking the active-site cysteine and C-terminal helices — engages two spatially distinct ligands at independent sites: monoubiquitin via the Ile44 surface and PTAP/PSAP tetrapeptide motifs in a hydrophobic SH3/WW-like pocket (PMID:12006492, PMID:12379843, PMID:15053872). Through these surfaces TSG101 recognizes ubiquitylated cargo and is recruited to endosomal membranes by the PSAP motif of the ESCRT-0 adaptor HRS, then assembles with VPS28 into the ~350 kDa ESCRT-I complex to deliver cargo such as EGFR and connexins to late endosomes/lysosomes in a VPS4-dependent manner (PMID:11134028, PMID:12802020, PMID:12900394, PMID:19808888). This same cargo-recognition activity is usurped by enveloped viruses: the PTAP late domain of HIV-1 Gag and PTAP-like motifs of Ebola VP40 and HBV capsid directly bind the UEV domain to recruit ESCRT-I and complete budding (PMID:11595185, PMID:11726971, PMID:11427703, PMID:37224147). TSG101 likewise mediates plasma-membrane ARMM budding via ARRDC1 and acts as a positive regulator of intraluminal vesicle formation, antagonized by ALIX, which competes for the UEV peptide-binding site and is bridged to TSG101 by Ca2+-loaded ALG-2 (PMID:18768755, PMID:22315426, PMID:32917811, PMID:19520058). Beyond canonical sorting, TSG101 performs ESCRT-independent functions: in the nucleus it binds PARP1 and is required for PARP1 activation, NF-κB signaling after DNA damage, and synthetic lethality in BRCA1/2-deficient cells (PMID:36124865); in axons it suppresses PGC-1α/Nrf2-driven mitochondrial biogenesis (PMID:33972422); and at lipid droplet–mitochondria contacts it cooperates with VPS13D to remodel membranes for fatty-acid transfer (PMID:33623047). Its own abundance is set by a C-terminal 'steadiness box' through which the E3 ligases Tal and MGRN1 monoubiquitinate TSG101, with non-ESCRT-incorporated TSG101 polyubiquitinated for proteasomal degradation unless protected by VPS28/ESCRT-I assembly (PMID:15256501, PMID:17229889, PMID:18077552). TSG101 loss in vivo stabilizes p53, and a p53-null background rescues the gastrulation defect of TSG101-null embryos, linking it genetically to the p53 pathway (PMID:11172041).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 Medium

    Established TSG101's cell-cycle-dependent subcellular distribution and a role in genome stability, raising the question of its biochemical activity.

    Evidence Immunofluorescence across the cell cycle and phenotyping of deficient cells

    PMID:9465061

    Open questions at the time
    • No molecular mechanism for spindle/centrosome function
    • Relationship to later ESCRT role unresolved
  2. 2000 High

    Identified TSG101 as a VPS23 ortholog acting in late-endosomal cargo delivery and showed its abundance is set posttranslationally by a C-terminal steadiness box, defining its trafficking role and an autoregulatory layer.

    Evidence Trafficking assays in mutant cells; deletion mapping and pulse-chase; co-IP/cross-linking with VPS28

    PMID:10749147 PMID:11134028 PMID:11208108

    Open questions at the time
    • Steadiness-box ligase not yet identified
    • Mechanism of cargo selection not yet structural
  3. 2001 High

    Defined the UEV domain as a catalytically inactive E2 variant that binds ubiquitin and PTAP late domains, establishing TSG101/ESCRT-I as the cellular machinery hijacked for HIV-1 and Ebola budding.

    Evidence siRNA depletion with rescue, binding assays, dominant-negative VPS4, EM; site-directed mutagenesis of Tyr-110

    PMID:11427703 PMID:11595185 PMID:11726971

    Open questions at the time
    • Atomic basis of dual-ligand recognition not yet solved
    • Composition of full ESCRT-I in budding incomplete
  4. 2001 High

    Linked TSG101 to the p53/MDM2 axis in vivo, showing its loss stabilizes p53 and that p53 ablation rescues the null embryonic phenotype.

    Evidence Knockout and double-knockout mice with genetic epistasis; MDM2/p53 biochemistry

    PMID:11172000 PMID:11172041

    Open questions at the time
    • Direct mechanism of MDM2 ubiquitination interference not reconstituted
    • Whether this is ESCRT-dependent unclear
  5. 2002 High

    Solved UEV-domain structures alone, with PTAP peptide, establishing distinct, independent binding pockets for peptide ligands and the vestigial active site.

    Evidence NMR structures with SPR/chemical-shift mapping

    PMID:12006492 PMID:12379843

    Open questions at the time
    • Ubiquitin-binding geometry not yet co-crystallized (resolved later)
  6. 2003 High

    Identified HRS as the physiological PSAP adaptor recruiting TSG101 to endosomes, explaining how cellular cargo sorting and viral budding share the same recruitment logic.

    Evidence Reciprocal co-IP, yeast two-hybrid, functional rescue and EGFR trafficking assays

    PMID:12802020 PMID:12900394

    Open questions at the time
    • Stoichiometry of HRS-TSG101 handoff unclear
    • How ubiquitin and PSAP binding are coordinated unresolved
  7. 2004 High

    Determined the UEV-ubiquitin co-crystal structure and identified Tal as an E3 ligase that monoubiquitinates TSG101, defining both the ubiquitin-recognition interface and a regulatory ubiquitination input.

    Evidence X-ray crystallography with mutagenesis/MVB assays; in vitro ubiquitination and domain mapping

    PMID:15053872 PMID:15256501

    Open questions at the time
    • Functional consequence of monoubiquitination not fully defined here
    • Whether Tal acts on assembled vs free TSG101 unclear
  8. 2006 High

    Distinguished TSG101's role in MVB formation itself from HRS's role in ILV accumulation, separating ESCRT-I and ESCRT-0 functions.

    Evidence siRNA with EM and EGF-degradation assays

    PMID:16707569

    Open questions at the time
    • Biophysical mechanism of membrane deformation not addressed
  9. 2007 High

    Showed MGRN1 (Mahogunin) monoubiquitinates TSG101 and that the steadiness box governs Tal-mediated polyubiquitination/degradation gated by VPS28 availability, defining how ESCRT-I assembly protects TSG101.

    Evidence In vitro ubiquitination, proteasome inhibition, siRNA, co-IP

    PMID:17229889 PMID:18077552

    Open questions at the time
    • Switch between mono- and poly-ubiquitination not fully resolved
    • In vivo relevance of feedback loop untested
  10. 2008 Medium

    Reconstituted ILV budding in vitro and assigned TSG101 a positive regulatory role antagonized by ALIX; extended ESCRT-I function to viral nucleocapsid back-fusion.

    Evidence Cell-free budding reconstitution; VSV infection and endosomal fractionation

    PMID:18768755 PMID:18817529

    Open questions at the time
    • Molecular basis of ALIX antagonism not yet structural (resolved 2020)
    • Back-fusion mechanism single-lab
  11. 2012 Medium

    Generalized TSG101 recruitment beyond endosomes to direct plasma-membrane ARMM budding via ARRDC1 and to midbody/cytokinesis via Rab11-FIP coiled-coil interactions.

    Evidence Co-IP, mutagenesis, live imaging, EM; cytokinesis phenotyping

    PMID:22315426 PMID:22348143

    Open questions at the time
    • FIP4 interaction dispensable for midbody localization, leaving recruitment mechanism open
    • ARMM cargo selectivity unclear
  12. 2020 Medium

    Resolved how ALIX competes with itself and TSG101 at the UEV peptide site and uncovered a p62/Keap1/Nrf2 cardioprotective signaling role, broadening TSG101 function.

    Evidence NMR relaxation dispersion; co-IP, domain mapping, p62-knockout mice

    PMID:32057709 PMID:32917811

    Open questions at the time
    • Physiological balance of ALIX vs cargo competition in cells unmeasured
    • Direct vs indirect p62 effects not fully separated
  13. 2021 High

    Defined two ESCRT-independent functions: lipid-droplet-to-mitochondria fatty-acid transfer with VPS13D, and suppression of axonal mitochondrial biogenesis via PGC-1α/Nrf2.

    Evidence In vitro LD remodeling and lipid transfer; Drosophila forward genetic screen with ESCRT epistasis

    PMID:33623047 PMID:33972422

    Open questions at the time
    • How a single protein partitions between ESCRT and non-ESCRT pools unknown
    • Direct biochemical activity in mitochondrial biogenesis suppression undefined
  14. 2022 High

    Established a nuclear, ESCRT-independent role in which TSG101 binds and activates PARP1 to drive NF-κB signaling and confers synthetic lethality in BRCA1/2-deficient cells.

    Evidence Genome-wide siRNA screen, co-IP, PAR and NF-κB assays, synthetic-lethality assays

    PMID:36124865

    Open questions at the time
    • How TSG101 mechanistically promotes PARP1 catalysis unresolved
    • Nuclear targeting signal/regulation not defined
  15. 2023 High

    Extended viral-egress recruitment to HBV, requiring NEDD4/UbcH6-catalyzed ubiquitination of the HBc capsid and a VFND motif in TSG101.

    Evidence In vitro ubiquitination, mutagenesis, siRNA, EM, transgenic mouse

    PMID:37224147

    Open questions at the time
    • Structural basis of VFND-mediated contact undefined
    • Whether full ESCRT-I is required for HBV release untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TSG101 is partitioned and regulated between ESCRT-I-bound cytoplasmic pools and its ESCRT-independent nuclear, axonal, and membrane-contact-site roles remains unresolved.
  • No mechanism for nuclear import/retention
  • No structure of full ESCRT-I human complex in the timeline
  • Determinants directing TSG101 to non-ESCRT functions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0031386 protein tag activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 1
Localization
GO:0005768 endosome 3 GO:0005634 nucleus 2 GO:0005811 lipid droplet 1 GO:0005815 microtubule organizing center 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 2 R-HSA-73894 DNA Repair 1
Partners
ALG-2ALIXARRDC1HRSMGRN1PARP1VPS13DVPS28
Complex memberships
ESCRT-I

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 The UEV (ubiquitin E2 variant) domain of TSG101 directly binds the PTAP tetrapeptide 'late domain' motif of HIV-1 Gag p6 protein, and also binds ubiquitin. Depletion of TSG101 by siRNA arrests HIV-1 budding at a late stage; reintroduction rescues budding. Dominant-negative VPS4 also arrests HIV-1 budding, placing TSG101 in the vacuolar protein sorting (VPS)/ESCRT pathway required for HIV-1 egress. siRNA depletion, co-immunoprecipitation, surface plasmon resonance binding assay, dominant-negative VPS4 overexpression, electron microscopy Cell High 11595185
2001 TSG101 interacts with the PTAP-containing late domain of HIV-1 Gag and the PTAP-like motif of Ebola VP40 (EbVp40). Recruitment of TSG101 to assembling virions restores budding competence to late-domain-defective HIV-1, establishing that TSG101 recruitment is the essential function of the viral late domain. Co-immunoprecipitation, dominant-negative TSG101 overexpression, functional rescue assay, confocal microscopy Nature medicine High 11726971
2001 TSG101 binds to the PTAP motif of HIV-1 Gag p6 through its N-terminal UBC-like domain. Mutation of Tyr-110 (in place of the active-site Cys present in canonical E2 enzymes) and surrounding residues unique to TSG101 impairs p6 binding, showing that TSG101 is a catalytically inactive E2 variant whose distinctive features mediate viral protein interaction. Yeast two-hybrid, in vitro co-immunoprecipitation with purified proteins, in vivo co-immunoprecipitation in COS cells, site-directed mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 11427703
2000 TSG101 (mammalian VPS23) functions in late endosomal trafficking. TSG101 mutant cells show defects in cathepsin D sorting/maturation, mislocalization of mannose-6-phosphate receptor, and recycling of endocytosed EGF receptors back to the cell surface instead of lysosomal delivery, demonstrating TSG101 is required for cargo delivery to late endosomes/MVBs. Cell fractionation, Western blotting, receptor trafficking assays in TSG101 mutant cells, pulse-chase Traffic (Copenhagen, Denmark) High 11208108
2002 The crystal/NMR structure of the TSG101 UEV domain reveals it resembles canonical E2 ubiquitin-conjugating enzymes but has an additional N-terminal helix, an extended beta-hairpin, and lacks two C-terminal helices. PTAP peptides bind in a hydrophobic cleft exposed by the absence of C-terminal helices; ubiquitin binds at a novel site surrounding the beta-hairpin. These two binding sites are spatially distinct and independent. NMR structure determination, chemical shift mapping, surface plasmon resonance binding assays The EMBO journal High 12006492
2002 Solution structure of the TSG101 UEV domain in complex with the HIV-1 p6 PTAP peptide shows that each PTAP residue makes important contacts; the Ala-Pro dipeptide binds in a deep pocket resembling the X-Pro binding pockets of SH3 and WW domains, located above the vestigial active site. NMR solution structure determination Nature structural biology High 12379843
2004 Crystal structure of the TSG101 UEV domain in complex with ubiquitin at 2.0 Å resolution shows TSG101 UEV contacts the Ile44 surface and an adjacent loop of ubiquitin through a highly solvated interface. Mutations disrupting this interface inhibit MVB sorting, and the ubiquitin-binding site is distinct from the PTAP-binding site, allowing independent binding of both ligands. X-ray crystallography, site-directed mutagenesis, functional MVB sorting assays Molecular cell High 15053872
2000 TSG101 directly interacts with mammalian VPS28 (hVPS28) through the conserved C-terminal portion of TSG101 to form part of a multiprotein complex (~350 kDa). Upon expression of dominant-negative VPS4, a portion of TSG101 and hVPS28 translocate from cytosol to the surface of aberrant endosomal vacuoles. Co-immunoprecipitation, chemical cross-linking, gel filtration, confocal microscopy with dominant-negative VPS4 The Journal of biological chemistry High 11134028
2003 TSG101 interacts with HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) via the UEV domain of TSG101 binding to two proline-rich regions of HRS including a PSAP motif. Disruption of this interaction prevents delivery of EGFR to late endosomes, causes accumulation of ubiquitinated EGFR in early endosomes, and inhibits ligand-induced EGFR down-regulation. Co-immunoprecipitation, deletion/mutagenesis analysis, confocal microscopy, receptor trafficking assays Proceedings of the National Academy of Sciences of the United States of America High 12802020
2003 HIV-1 Gag mimics the Tsg101-recruiting activity of the endosomal protein Hrs. The Tsg101 UEV domain binds the PSAP motif (residues 348-351) within Hrs, and Hrs residues 222-777 can recruit Tsg101 and rescue budding of Gag particles lacking native late domains, demonstrating that Hrs normally recruits Tsg101 to the endosomal membrane and HIV Gag usurps this activity. Co-immunoprecipitation, yeast two-hybrid, functional rescue assay, dominant-negative competition The Journal of cell biology High 12900394
2001 TSG101 participates in an autoregulatory loop with MDM2: the UBC domain of TSG101 interferes with ubiquitination of MDM2, stabilizing MDM2 and thereby down-regulating p53 protein levels. Conversely, elevated MDM2 promotes TSG101 degradation via the 26S proteasome. Pulse-chase analysis, Western blotting in wild-type and mutant fibroblasts, ubiquitination assays, MDM2/p53 overexpression experiments Proceedings of the National Academy of Sciences of the United States of America Medium 11172000
2001 TSG101 null embryos accumulate p53 protein (without change in p53 mRNA), and introduction of a p53 null mutation into tsg101-/- embryos rescues the gastrulation defect and extends survival, establishing a functional genetic link between TSG101 and the p53 pathway in vivo. Gene targeting (knockout mice), genetic epistasis (double knockout), Western blotting, in vivo embryo analysis Proceedings of the National Academy of Sciences of the United States of America High 11172041
2002 Ubiquitylation of MHC class I by the Kaposi's sarcoma herpesvirus K3 protein requires TSG101 for subsequent degradation in the late endocytic pathway. siRNA depletion of TSG101 prevents MHC class I degradation and preserves its cell surface expression in K3-expressing cells. siRNA knockdown, flow cytometry, Western blotting, confocal microscopy The EMBO journal Medium 12006494
2004 Tal (Tsg101-associated ligase) is an E3 ubiquitin ligase whose RING finger mediates multiple monoubiquitylation of TSG101. Bivalent binding of TSG101 to a tandem PTAP motif and a central region of Tal is required for Tal-mediated TSG101 ubiquitylation. Tal regulates a TSG101-associated complex responsible for sorting cargo into MVB vesicles and plasma membrane budding. Co-immunoprecipitation, in vitro ubiquitination assay, deletion/mutagenesis analysis, functional assays (EGFR endocytosis, HIV egress) Genes & development High 15256501
2007 Mahogunin E3 ubiquitin ligase interacts with the UEV domain of TSG101 via its PSAP motif and catalyzes monoubiquitylation of TSG101 both in vivo and in vitro. Depletion of Mahogunin disrupts endosome-to-lysosome trafficking of EGFR, resulting in prolonged downstream signaling. Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown, EGFR trafficking assays Molecular biology of the cell High 17229889
2007 The steadiness box (conserved C-terminal sequence) of TSG101 controls its steady-state level. Tal polyubiquitinates lysine residues in the C-terminus of TSG101 not complexed with other ESCRT-I proteins, leading to proteasomal degradation. VPS28 is a limiting factor, and ESCRT-I complex assembly protects TSG101 from Tal-mediated degradation. Ubiquitination assays, proteasome inhibitor experiments, siRNA knockdown, co-immunoprecipitation, Western blotting Molecular biology of the cell High 18077552
2000 The TSG101 protein steady-state level is controlled posttranslationally by an evolutionarily conserved C-terminal sequence termed the 'steadiness box.' Overproduction of TSG101 from adventitious constructs results in compensatory down-regulation of endogenous TSG101 protein (not mRNA), through a proteolytic feedback loop involving the steadiness box. Western blotting, Northern blotting, deletion mapping of TSG101 constructs, pulse-chase in cultured cells Cancer research Medium 10749147
1998 TSG101 localization is cell cycle-dependent: it localizes to the nucleus and Golgi complex during interphase, and to mitotic spindles and centrosomes during mitosis. TSG101-deficient cells display multiple microtubule organizing centers, aberrant mitotic spindles, aneuploidy, and nuclear anomalies. Indirect immunofluorescence, cell fractionation, FACS analysis Proceedings of the National Academy of Sciences of the United States of America Medium 9465061
2006 Depletion of TSG101 inhibits EGF-stimulated MVB formation (number of MVBs per unit cytoplasm), causes tubulation of the early endosome vacuolar domains, and potently inhibits EGF degradation; this is distinct from the role of Hrs, which is required for accumulation of internal vesicles within MVBs but not MVB formation itself. siRNA depletion, electron microscopy, confocal microscopy, EGF degradation assays Molecular biology of the cell High 16707569
2008 In a cell-free reconstitution assay, the ESCRT-I subunit Tsg101 acts as a positive regulator of intraluminal vesicle (ILV) formation within late endosomes, while Alix acts as a negative regulator; ILV budding is inhibited by dominant-negative VPS4, confirming ESCRT dependence. In vitro budding reconstitution assay, dominant-negative mutant analysis, quantitative biochemistry Molecular biology of the cell High 18768755
2010 TSG101 and ubiquitin are required for cSMAC formation at the immunological synapse. siRNA knockdown of TSG101 in primary T cells impairs cSMAC formation, TCR microcluster signal termination, TCR downregulation, and segregation of TCR-MHC-peptide from PKC-theta complexes, demonstrating that ubiquitin recognition by TSG101 is a molecular checkpoint for TCR downregulation. siRNA knockdown in primary T cells, live imaging of immunological synapses, TIRF microscopy, flow cytometry Immunity High 20399684
2012 TSG101 is recruited to the plasma membrane by binding the PSAP motif of the arrestin-domain protein ARRDC1, which drives direct plasma membrane budding to form ARRDC1-mediated microvesicles (ARMMs). This process requires VPS4 ATPase activity and is enhanced by the E3 ligase WWP2, which ubiquitinates ARRDC1. Co-immunoprecipitation, mutagenesis, live cell imaging, electron microscopy, siRNA knockdown Proceedings of the National Academy of Sciences of the United States of America High 22315426
2004 TSG101 interacts with AATF and functions as a cooperative coactivator of androgen receptor-mediated transcription. TSG101 enhances monoubiquitination of the androgen receptor in a ligand-dependent manner, correlating with enhanced transactivating capacity. Co-immunoprecipitation, reporter gene assays, in vivo ubiquitination assay, dominant-negative ubiquitin overexpression The Journal of biological chemistry Medium 14761944
2002 TSG101 binds p21(Cip1/WAF1) and increases p21 protein stability in HEK293F cells and differentiating keratinocytes. In proliferating keratinocytes, TSG101 is recruited in a p21-dependent manner to cyclin/CDK complexes and inhibits cyclin/CDK activity, causing growth suppression. Co-immunoprecipitation, pulse-chase protein stability assays, kinase activity assays, antisense RNA knockdown, cell cycle analysis Proceedings of the National Academy of Sciences of the United States of America Medium 11943869
2005 ALG-2 (a penta-EF-hand Ca2+-binding protein) directly binds the proline-rich region (PRR) of TSG101 in a Ca2+-dependent manner, as shown by GST pulldown and yeast two-hybrid. ALG-2 co-localizes with TSG101 at aberrant endosomes induced by dominant-negative SKD1/Vps4B, and this localization is Ca2+-dependent. GST pulldown, yeast two-hybrid, overlay assay with biotinylated ALG-2, immunofluorescence microscopy, deletion mapping The Biochemical journal Medium 16004603
2005 TSG101 stabilizes the unliganded (hypophosphorylated) form of the glucocorticoid receptor (GR) by impeding its proteasomal degradation and extending its half-life. The non-phosphorylated GR (S203A/S211A mutant) shows enhanced interaction with TSG101, and siRNA depletion of TSG101 renders hypophosphorylated GR unstable. Co-immunoprecipitation, siRNA knockdown, pulse-chase analysis, proteasome inhibitor experiments, site-directed mutagenesis The Journal of biological chemistry Medium 15657031
2021 VPS13D directly interacts with TSG101 through its adaptor-binding domain, and together they remodel lipid droplet (LD) membranes to facilitate transfer of fatty acids from LDs to mitochondria at membrane contact sites. Depletion of TSG101 or VPS13D or ESCRT-III proteins inhibits fatty acid trafficking from LDs to mitochondria. Co-immunoprecipitation, in vitro LD membrane remodeling assay, lipid transfer binding assays, siRNA knockdown, live cell imaging Nature communications High 33623047
2009 TSG101 and Hrs are required for trafficking of ubiquitylated connexin-43 (Cx43) from early endosomes to lysosomes. siRNA depletion of Hrs or TSG101 individually abrogates Cx43 trafficking to lysosomes; simultaneous depletion causes accumulation of phosphorylated and ubiquitylated Cx43 in early endosomes. siRNA knockdown, confocal microscopy, Western blotting, protein half-life measurement, microinjected Lucifer yellow transfer assays Journal of cell science Medium 19808888
2009 ALG-2 bridges Alix and TSG101 as a Ca2+-dependent adaptor. ALG-2 is required for Ca2+-dependent pulldown of TSG101 by Strep-Alix; this bridge requires the ALG-2 binding site of Alix but not the PSAP motif; ALG-2 dimerization and Ca2+ binding are both required for bridging activity. Pulldown assays with purified proteins, ALG-2 knockdown, exogenous ALG-2 rescue, mutagenesis of ALG-2 Biochemical and biophysical research communications Medium 19520058
2008 TSG101 (ESCRT-I subunit) is required for nucleocapsid release from within multivesicular endosomes to the cytoplasm during vesicular stomatitis virus (VSV) infection, specifically by controlling the back-fusion of intra-endosomal vesicles with the endosome limiting membrane, independently of its role in viral envelope fusion. siRNA knockdown, infection assays, endosomal fractionation, functional infectivity measurements Traffic (Copenhagen, Denmark) Medium 18817529
2020 TSG101 interacts with SQSTM1/p62 through its PRR domain and promotes p62 aggregation, leading to recruitment of Keap1 for autophagic degradation and release of Nrf2 to the nucleus. Knockout of p62 abrogates TSG101-induced cardioprotective effects, establishing TSG101 as a regulator of the p62/Keap1/Nrf2 signaling cascade. Co-immunoprecipitation, domain deletion analysis, p62 knockout mice, transgenic and knockdown mouse models, RNA sequencing, pharmacological Nrf2 inhibition Redox biology Medium 32057709
2021 TSG101 negatively regulates mitochondrial biogenesis in axons through a non-canonical, ESCRT-independent mechanism. Loss of Tsg101 activates PGC-1α/Nrf2-dependent mitochondrial biogenesis in an mTOR-independent, TFEB-dependent manner that requires the mitochondrial fission-fusion machinery. Loss of other ESCRT components does not recapitulate this phenotype. In vivo forward genetic screen (Drosophila), genetic epistasis with other ESCRT components, mitophagy and autophagy blockade, live imaging of axonal mitochondria Proceedings of the National Academy of Sciences of the United States of America High 33972422
2022 TSG101 binds to PARP1 and is required for PARP1 activation and poly(ADP-ribose) (PAR) formation following DNA double-strand breaks. This TSG101 function is independent of its role in ESCRT-I. Absence of TSG101 impairs PAR-dependent formation of a nuclear PARP1-IKKγ signalosome, blocks IKK-NF-κB activation, causes PARP1 trapping at damage sites, and renders BRCA1/2-deficient cells synthetically lethal. Genome-wide siRNA screen, co-immunoprecipitation, PAR detection assays, NF-κB reporter assays, DNA repair assays, synthetic lethality assays The EMBO journal High 36124865
2009 TSG101 interacts with the coiled-coil domain of GISP (G protein-coupled receptor interacting scaffold protein) and mediates lysosomal degradation of GABA(B2) receptor. GISP overexpression inhibits TSG101-dependent GABA(B2) down-regulation, and a GISP mutant lacking the TSG101-binding domain has no protective effect. Co-immunoprecipitation from rat brain, GST pulldown, deletion mapping, siRNA/overexpression in HEK293 cells, receptor degradation assays Journal of neurochemistry Medium 18643869
2009 TSG101 interacts with multiple connexins (Cx31, Cx43, Cx45 confirmed by co-immunoprecipitation from embryonic stem cells). siRNA-mediated knockdown of TSG101 increases levels of Cx43 and Cx45, prolongs their half-life, and increases gap junction-mediated dye transfer. Yeast two-hybrid, GST pulldown, co-immunoprecipitation from HM1 ES cells, siRNA knockdown, Western blotting, Lucifer yellow transfer Experimental cell research Medium 19210987
2012 TSG101 interacts with the class II Rab11-FIPs (FIP3 and FIP4) through coiled-coil domains on both proteins. Point mutations in the coiled-coil regions of either TSG101 or FIP4 abrogate the interaction. Expression of TSG101 and FIP4 coiled-coil mutants causes cytokinesis defects, though the TSG101-FIP4 interaction is not required for TSG101 localization to the midbody during abscission. Proteomic screening, co-immunoprecipitation, site-directed mutagenesis, cytokinesis phenotype analysis, confocal microscopy PloS one Medium 22348143
2015 Mahogunin (MGRN1) ubiquitinates TSG101, and this monoubiquitination is required for fusion of lysosomes with autophagosomes (via amphisomes) and late endosomes. Catalytically inactive MGRN1 or depletion of MGRN1 blocks these fusion events. Overexpression of TSG101 or its monoubiquitinated form rescues lysosomal fusion in MGRN1-deficient cells. In vivo and in vitro ubiquitination assays, siRNA knockdown, rescue by TSG101 overexpression, autophagy flux assays, lysosomal fusion assays Cell death & disease Medium 26539917
2020 ALIX proline-rich domain (PRD) contains three tandem proline-rich motifs that compete for a single binding site on TSG101-UEV, as demonstrated by NMR relaxation dispersion and global fitting. This competitive interaction modulates ALIX function in ESCRT-mediated membrane remodeling. NMR spectroscopy (heteronuclear, relaxation dispersion), quantitative binding analysis by global fitting Proceedings of the National Academy of Sciences of the United States of America High 32917811
1998 TSG101 acts as a transcriptional suppressor through its coiled-coil domain. TSG101 represses estrogen receptor-mediated transcription and inhibits basal promoter activity; the coiled-coil domain is required for this repression and also for tumor suppressive function. Reporter gene transcription assays, deletion mutagenesis, histone acetyltransferase/deacetylase activity assays (negative result for these activities) Biochemical and biophysical research communications Medium 9588212
2023 TSG101 interacts with HBV capsid protein HBc via the VFND motif in TSG101 and Lys-96 ubiquitination in HBc. NEDD4 (E3) and UbcH6 (E2) catalyze HBc ubiquitination required for TSG101-HBc interaction. TSG101 or NEDD4 knockdown reduces HBV particle counts in MVBs and suppresses HBV release. Co-immunoprecipitation, site-directed mutagenesis, in vitro ubiquitination assay, siRNA knockdown, transmission electron microscopy, HBV transgenic mouse model PLoS pathogens High 37224147

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell 1169 11595185
2001 HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress. Nature medicine 615 11726971
2012 Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein. Proceedings of the National Academy of Sciences of the United States of America 580 22315426
2001 Tsg101, a homologue of ubiquitin-conjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55(Gag). Proceedings of the National Academy of Sciences of the United States of America 508 11427703
2000 Mammalian tumor susceptibility gene 101 (TSG101) and the yeast homologue, Vps23p, both function in late endosomal trafficking. Traffic (Copenhagen, Denmark) 360 11208108
1996 Tsg101: a novel tumor susceptibility gene isolated by controlled homozygous functional knockout of allelic loci in mammalian cells. Cell 310 8616888
2002 Overexpression of the N-terminal domain of TSG101 inhibits HIV-1 budding by blocking late domain function. Proceedings of the National Academy of Sciences of the United States of America 307 11805336
2003 TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation. Proceedings of the National Academy of Sciences of the United States of America 274 12802020
2002 Structure and functional interactions of the Tsg101 UEV domain. The EMBO journal 258 12006492
2003 Overlapping motifs (PTAP and PPEY) within the Ebola virus VP40 protein function independently as late budding domains: involvement of host proteins TSG101 and VPS-4. Journal of virology 234 12525615
2003 HIV Gag mimics the Tsg101-recruiting activity of the human Hrs protein. The Journal of cell biology 215 12900394
2002 Structure of the Tsg101 UEV domain in complex with the PTAP motif of the HIV-1 p6 protein. Nature structural biology 209 12379843
2006 Distinct roles for Tsg101 and Hrs in multivesicular body formation and inward vesiculation. Molecular biology of the cell 207 16707569
2004 Ubiquitin recognition by the human TSG101 protein. Molecular cell 182 15053872
2002 Ubiquitylation of MHC class I by the K3 viral protein signals internalization and TSG101-dependent degradation. The EMBO journal 170 12006494
2000 TSG101/mammalian VPS23 and mammalian VPS28 interact directly and are recruited to VPS4-induced endosomes. The Journal of biological chemistry 170 11134028
2003 Ebola virus matrix protein VP40 interaction with human cellular factors Tsg101 and Nedd4. Journal of molecular biology 161 12559917
2005 Depletion of TSG101 forms a mammalian "Class E" compartment: a multicisternal early endosome with multiple sorting defects. Journal of cell science 156 16014378
2001 A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control. Proceedings of the National Academy of Sciences of the United States of America 147 11172000
2007 Beyond Tsg101: the role of Alix in 'ESCRTing' HIV-1. Nature reviews. Microbiology 142 17982468
2001 p53 accumulation, defective cell proliferation, and early embryonic lethality in mice lacking tsg101. Proceedings of the National Academy of Sciences of the United States of America 137 11172041
2010 Essential role of ubiquitin and TSG101 protein in formation and function of the central supramolecular activation cluster. Immunity 133 20399684
2004 Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding. Genes & development 130 15256501
1997 The TSG101 tumor susceptibility gene is located in chromosome 11 band p15 and is mutated in human breast cancer. Cell 130 9019400
2004 Nedd4.1-mediated ubiquitination and subsequent recruitment of Tsg101 ensure HTLV-1 Gag trafficking towards the multivesicular body pathway prior to virus budding. Journal of cell science 128 15126635
2009 Herpes simplex virus type 1 production requires a functional ESCRT-III complex but is independent of TSG101 and ALIX expression. Journal of virology 127 19692479
2008 Inhibition of HIV budding by a genetically selected cyclic peptide targeting the Gag-TSG101 interaction. ACS chemical biology 121 19053244
2007 Spongiform neurodegeneration-associated E3 ligase Mahogunin ubiquitylates TSG101 and regulates endosomal trafficking. Molecular biology of the cell 121 17229889
2003 Tsg101 is essential for cell growth, proliferation, and cell survival of embryonic and adult tissues. Molecular and cellular biology 119 12482969
2021 An ESCRT-dependent step in fatty acid transfer from lipid droplets to mitochondria through VPS13D-TSG101 interactions. Nature communications 113 33623047
2006 An essential role for SNX1 in lysosomal sorting of protease-activated receptor-1: evidence for retromer-, Hrs-, and Tsg101-independent functions of sorting nexins. Molecular biology of the cell 113 16407403
2003 PPPYVEPTAP motif is the late domain of human T-cell leukemia virus type 1 Gag and mediates its functional interaction with cellular proteins Nedd4 and Tsg101 [corrected]. Journal of virology 113 14581525
2006 Nonstructural protein 3 of bluetongue virus assists virus release by recruiting ESCRT-I protein Tsg101. Journal of virology 112 16352570
1998 Cell cycle-dependent subcellular localization of the TSG101 protein and mitotic and nuclear abnormalities associated with TSG101 deficiency. Proceedings of the National Academy of Sciences of the United States of America 101 9465061
2007 Interaction of Tsg101 with Marburg virus VP40 depends on the PPPY motif, but not the PT/SAP motif as in the case of Ebola virus, and Tsg101 plays a critical role in the budding of Marburg virus-like particles induced by VP40, NP, and GP. Journal of virology 91 17301151
2008 In vitro budding of intralumenal vesicles into late endosomes is regulated by Alix and Tsg101. Molecular biology of the cell 89 18768755
2009 Ubiquitylation of the gap junction protein connexin-43 signals its trafficking from early endosomes to lysosomes in a process mediated by Hrs and Tsg101. Journal of cell science 86 19808888
2003 Defects in human immunodeficiency virus budding and endosomal sorting induced by TSG101 overexpression. Journal of virology 86 12743307
1997 Aberrant splicing of the TSG101 and FHIT genes occurs frequently in multiple malignancies and in normal tissues and mimics alterations previously described in tumours. Oncogene 86 9366528
1997 The breast cancer gene product TSG101: a regulator of ubiquitination? Journal of molecular medicine (Berlin, Germany) 85 9253709
2004 TSG101 interacts with apoptosis-antagonizing transcription factor and enhances androgen receptor-mediated transcription by promoting its monoubiquitination. The Journal of biological chemistry 84 14761944
2003 Tsg101 control of human immunodeficiency virus type 1 Gag trafficking and release. Journal of virology 81 12915533
2002 Targeted deletion of the Tsg101 gene results in cell cycle arrest at G1/S and p53-independent cell death. The Journal of biological chemistry 77 12205095
2002 Overexpression of tumor susceptibility gene TSG101 in human papillary thyroid carcinomas. Oncogene 70 12101421
2005 The penta-EF-hand protein ALG-2 interacts directly with the ESCRT-I component TSG101, and Ca2+-dependently co-localizes to aberrant endosomes with dominant-negative AAA ATPase SKD1/Vps4B. The Biochemical journal 69 16004603
2015 WASH and Tsg101/ALIX-dependent diversion of stress-internalized EGFR from the canonical endocytic pathway. Nature communications 66 26066081
2012 Cryptococcus neoformans requires the ESCRT protein Vps23 for iron acquisition from heme, for capsule formation, and for virulence. Infection and immunity 66 23132495
2007 Regulation of Tsg101 expression by the steadiness box: a role of Tsg101-associated ligase. Molecular biology of the cell 64 18077552
2005 SIMPLE interacts with NEDD4 and TSG101: evidence for a role in lysosomal sorting and implications for Charcot-Marie-Tooth disease. Journal of neuroscience research 64 16118794
2004 Cell cycle arrest and cell death are controlled by p53-dependent and p53-independent mechanisms in Tsg101-deficient cells. The Journal of biological chemistry 58 15210712
2000 TSG101 protein steady-state level is regulated posttranslationally by an evolutionarily conserved COOH-terminal sequence. Cancer research 57 10749147
2008 The ESCRT-I subunit TSG101 controls endosome-to-cytosol release of viral RNA. Traffic (Copenhagen, Denmark) 54 18817529
2007 Tsg101 is upregulated in a subset of invasive human breast cancers and its targeted overexpression in transgenic mice reveals weak oncogenic properties for mammary cancer initiation. Oncogene 52 17369844
2002 Negative regulation of cell growth and differentiation by TSG101 through association with p21(Cip1/WAF1). Proceedings of the National Academy of Sciences of the United States of America 52 11943869
1998 A putative tumor suppressor, TSG101, acts as a transcriptional suppressor through its coiled-coil domain. Biochemical and biophysical research communications 51 9588212
2014 Interaction with Tsg101 is necessary for the efficient transport and release of nucleocapsids in marburg virus-infected cells. PLoS pathogens 50 25330247
2003 Association of Japanese encephalitis virus NS3 protein with microtubules and tumour susceptibility gene 101 (TSG101) protein. The Journal of general virology 50 13679614
2004 Reduction of TSG101 protein has a negative impact on tumor cell growth. International journal of cancer 49 14991575
1998 Perturbation of TSG101 protein affects cell cycle progression. Cancer research 49 9661875
2009 Penta-EF-hand protein ALG-2 functions as a Ca2+-dependent adaptor that bridges Alix and TSG101. Biochemical and biophysical research communications 47 19520058
2020 Tsg101 positively regulates P62-Keap1-Nrf2 pathway to protect hearts against oxidative damage. Redox biology 46 32057709
2002 Tsg101: HIV-1's ticket to ride. Trends in microbiology 46 11973141
1997 Frequent abnormalities of TSG101 transcripts in human prostate cancer. Oncogene 46 9444960
2009 Abnormal regulation of TSG101 in mice with spongiform neurodegeneration. Biochimica et biophysica acta 45 19703557
2005 The functionally exchangeable L domains in RSV and HIV-1 Gag direct particle release through pathways linked by Tsg101. Traffic (Copenhagen, Denmark) 44 16138902
2006 Vpu and Tsg101 regulate intracellular targeting of the human immunodeficiency virus type 1 core protein precursor Pr55gag. Journal of virology 43 16571793
2005 Stabilization of the unliganded glucocorticoid receptor by TSG101. The Journal of biological chemistry 41 15657031
2015 Mahogunin regulates fusion between amphisomes/MVBs and lysosomes via ubiquitination of TSG101. Cell death & disease 39 26539917
2007 Involvement of vacuolar protein sorting pathway in Ebola virus release independent of TSG101 interaction. The Journal of infectious diseases 38 17940959
1998 Genomic architecture and transcriptional activation of the mouse and human tumor susceptibility gene TSG101: common types of shorter transcripts are true alternative splice variants. Oncogene 38 9840940
2006 Role of the TSG101 gene in Epstein-Barr virus late gene transcription. Journal of virology 37 17182691
2016 Nipah Virus C Protein Recruits Tsg101 to Promote the Efficient Release of Virus in an ESCRT-Dependent Pathway. PLoS pathogens 36 27203423
2009 The TSG101 protein binds to connexins and is involved in connexin degradation. Experimental cell research 36 19210987
2022 The Neuroprotective Effects of Exosomes Derived from TSG101-Overexpressing Human Neural Stem Cells in a Stroke Model. International journal of molecular sciences 34 36076942
2020 The Multifaceted Roles of the Tumor Susceptibility Gene 101 (TSG101) in Normal Development and Disease. Cancers 34 32075127
2019 Circadian variation in the release of small extracellular vesicles can be normalized by vesicle number or TSG101. American journal of physiology. Renal physiology 33 31390267
2016 ESCRT-I Protein Tsg101 Plays a Role in the Post-macropinocytic Trafficking and Infection of Endothelial Cells by Kaposi's Sarcoma-Associated Herpesvirus. PLoS pathogens 33 27764233
2023 Hepatitis B virus hijacks TSG101 to facilitate egress via multiple vesicle bodies. PLoS pathogens 31 37224147
2010 TSG101: a novel anti-HIV-1 drug target. Current medicinal chemistry 30 20088757
2008 Tsg101 can replace Nedd4 function in ASV Gag release but not membrane targeting. Virology 30 18555885
2014 A unique N-terminal sequence in the Carnation Italian ringspot virus p36 replicase-associated protein interacts with the host cell ESCRT-I component Vps23. Journal of virology 29 24672030
2011 Down-regulation of TSG101 by small interfering RNA inhibits the proliferation of breast cancer cells through the MAPK/ERK signal pathway. Histology and histopathology 29 21117030
2020 Proline-rich domain of human ALIX contains multiple TSG101-UEV interaction sites and forms phosphorylation-mediated reversible amyloids. Proceedings of the National Academy of Sciences of the United States of America 28 32917811
2021 The ESCRT-I Subunit Tsg101 Plays Novel Dual Roles in Entry and Replication of Classical Swine Fever Virus. Journal of virology 27 33328308
2013 RAB7 and TSG101 are required for the constitutive recycling of unliganded EGFRs via distinct mechanisms. Molecular and cellular endocrinology 27 23933150
2006 The C-terminal portion of the Hrs protein interacts with Tsg101 and interferes with human immunodeficiency virus type 1 Gag particle production. Journal of virology 27 17182674
2014 HIV-1 nucleocapsid and ESCRT-component Tsg101 interplay prevents HIV from turning into a DNA-containing virus. Nucleic acids research 26 25488808
2012 Tumor susceptibility gene 101 (TSG101) is a novel binding-partner for the class II Rab11-FIPs. PloS one 26 22348143
2008 Overexpression of WNT2 and TSG101 genes in colorectal carcinoma. Tropical biomedicine 26 18600204
2022 TSG101 associates with PARP1 and is essential for PARylation and DNA damage-induced NF-κB activation. The EMBO journal 25 36124865
2020 MiR-17-5p-mediated endoplasmic reticulum stress promotes acute myocardial ischemia injury through targeting Tsg101. Cell stress & chaperones 25 32895884
2008 GISP binding to TSG101 increases GABA receptor stability by down-regulating ESCRT-mediated lysosomal degradation. Journal of neurochemistry 25 18643869
2018 TSG101 promotes the proliferation, migration and invasion of hepatocellular carcinoma cells by regulating the PEG10. Journal of cellular and molecular medicine 24 30450735
2021 TSG101 negatively regulates mitochondrial biogenesis in axons. Proceedings of the National Academy of Sciences of the United States of America 23 33972422
1997 Identification of cellular TSG101 protein in multiple human breast cancer cell lines. Cancer research 23 9331081
2013 Role of TSG101 in cancer. Frontiers in bioscience (Landmark edition) 22 23276921
2012 A knockout of the Tsg101 gene leads to decreased expression of ErbB receptor tyrosine kinases and induction of autophagy prior to cell death. PloS one 22 22479596
2009 Proline-rich sequence recognition: II. Proteomics analysis of Tsg101 ubiquitin-E2-like variant (UEV) interactions. Molecular & cellular proteomics : MCP 22 19542561
2004 Physical and functional interactions between Daxx and TSG101. Biochemical and biophysical research communications 21 15033475
1998 Aberrant splicing of the TSG101 tumor suppressor gene in human breast and ovarian cancers. Journal of the Society for Gynecologic Investigation 21 9773405

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