TSG101

Summary

TSG101 (tumor susceptibility 101, HGNC:15971) is a protein-coding gene on chromosome 11p15.1, encoding Tumor susceptibility gene 101 protein (Q99816). Component of the ESCRT-I complex, a regulator of vesicular trafficking process. It is a common-essential gene (DepMap: required in 97.3% of cancer cell lines).

The protein encoded by this gene belongs to a group of apparently inactive homologs of ubiquitin-conjugating enzymes. The gene product contains a coiled-coil domain that interacts with stathmin, a cytosolic phosphoprotein implicated in tumorigenesis. The protein may play a role in cell growth and differentiation and act as a negative growth regulator. In vitro steady-state expression of this tumor susceptibility gene appears to be important for maintenance of genomic stability and cell cycle regulation. Mutations and alternative splicing in this gene occur in high frequency in breast cancer and suggest that defects occur during breast cancer tumorigenesis and/or progression.

Source: NCBI Gene 7251 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 59 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.3% of screened cell lines (common-essential)
• MANE Select transcript: NM_006292

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15971
Approved symbol	TSG101
Name	tumor susceptibility 101
Location	11p15.1
Locus type	gene with protein product
Status	Approved
Aliases	VPS23
Ensembl gene	ENSG00000074319
Ensembl biotype	protein_coding
OMIM	601387
Entrez	7251

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 15 protein_coding, 5 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000251968, ENST00000438874, ENST00000535077, ENST00000536719, ENST00000540555, ENST00000542488, ENST00000543054, ENST00000543087, ENST00000544804, ENST00000545247, ENST00000580814, ENST00000584526, ENST00000860301, ENST00000860302, ENST00000860303, ENST00000860304, ENST00000860305, ENST00000860306, ENST00000860307, ENST00000860308, ENST00000930643, ENST00000930644, ENST00000930645, ENST00000930646, ENST00000941965

RefSeq mRNA: 1 — MANE Select: NM_006292 NM_006292

CCDS: CCDS7842

Canonical transcript exons

ENST00000251968 — 10 exons

Exon	Start	End
ENSE00001106772	18483870	18484072
ENSE00001106781	18480311	18480635
ENSE00001106782	18481630	18481869
ENSE00002295781	18526775	18526942
ENSE00003488053	18516099	18516164
ENSE00003502844	18509542	18509665
ENSE00003596637	18506857	18506923
ENSE00003615065	18502486	18502577
ENSE00003679322	18514678	18514841
ENSE00003686379	18519519	18519603

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.5321 / max 480.2266, expressed in 1815 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118943	27.8680	1812
118942	1.4564	850
118941	0.9715	642
118939	0.4421	155
118940	0.2721	85
118937	0.2573	67
206219	0.1602	35
206220	0.0820	30
118938	0.0225	8

Top tissues by expression

300 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.29	gold quality
secondary oocyte	CL:0000655	99.22	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.95	gold quality
ganglionic eminence	UBERON:0004023	97.37	gold quality
cortical plate	UBERON:0005343	97.35	gold quality
adrenal tissue	UBERON:0018303	97.26	gold quality
islet of Langerhans	UBERON:0000006	97.15	gold quality
amniotic fluid	UBERON:0000173	96.79	gold quality
lower esophagus mucosa	UBERON:0035834	96.39	gold quality
gastrocnemius	UBERON:0001388	96.30	gold quality
gingiva	UBERON:0001828	96.30	gold quality
gingival epithelium	UBERON:0001949	96.30	gold quality
rectum	UBERON:0001052	96.27	gold quality
muscle of leg	UBERON:0001383	96.22	gold quality
esophagus mucosa	UBERON:0002469	96.15	gold quality
parotid gland	UBERON:0001831	96.06	gold quality
right uterine tube	UBERON:0001302	96.05	gold quality
right adrenal gland cortex	UBERON:0035827	96.04	gold quality
esophagus squamous epithelium	UBERON:0006920	96.03	gold quality
colonic epithelium	UBERON:0000397	96.01	gold quality
right adrenal gland	UBERON:0001233	95.93	gold quality
epithelium of esophagus	UBERON:0001976	95.92	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	95.89	gold quality
skin of leg	UBERON:0001511	95.75	gold quality
left adrenal gland	UBERON:0001234	95.70	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.55	gold quality
muscle organ	UBERON:0001630	95.54	gold quality
metanephros cortex	UBERON:0010533	95.54	gold quality
squamous epithelium	UBERON:0006914	95.53	gold quality
adrenal gland	UBERON:0002369	95.52	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6142	no	540.98
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
CEP55	Unknown
EGFR	Repression
REG4	Repression

Upstream regulators (CollecTRI, top): MAZ, SP1, TTF2

miRNA regulators (miRDB)

45 targeting TSG101, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-548AV-3P	99.43	68.50	1721

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• TSG101 expression in gynecological tumors: relationship to cyclin D1, cyclin E, p53 and p16 proteins. (PMID:11838966)
• recognize ubiquitin and act in the removal of endosomal protein-ubiquitin conjugates. (PMID:11916981)
• Negative regulation of cell growth and differentiation by TSG101 through association with p21(Cip1/WAF1). (PMID:11943869)
• structure and functional interactions of its binding sites (PMID:12006492)
• solution structure of the UEV (ubiquitin E2 variant) binding domain of Tsg101 in complex with a PTAP peptide that spans the late domain of HIV-1 p6(Gag) (PMID:12379843)
• interacts specifically with human immunodeficiency virus type 2 gag polyprotein, results in increased levels of ubiquinated gag, and is incorporated into HIV-2 virions (PMID:12388682)
• Analysis of BRCA1, TP53, and TSG101 germline mutations in German breast and/or ovarian cancer families. (PMID:12505256)
• Human ortholog TSG101 does not substitute VPS23 in its ability to rescue the phenotype of defective plasma membrane proteins (PMID:12725919)
• truncated and full length forms of TSG101 inhibit HIV-1 budding by interacting with the p6 L domain and by disrupting the cellular endosomal sorting machinery (PMID:12743307)
• the TSG101 interaction with HRS is a crucial step in endocytic down-regulation of mitogenic signaling and this interaction may have a role in linking the functions of early and late endosomes (PMID:12802020)
• alternative splicing and role implicated in interaction with HIV-1 (PMID:14526201)
• TSG101 activates androgen receptor-induced transcription by transient stabilization of the monoubiquitinated state (PMID:14761944)
• Reduction of TSG101 protein has a negative impact on breast and prostate tumor cell growth (PMID:14991575)
• molecular interactions between Daxx and TSG101 establish an efficient repressive transcription complex in the nucleus (PMID:15033475)
• X-ray crystallography study of the UEV domain of TSG101 and ubquitin showed the basis for the binding recognition at high resolution. (PMID:15053872)
• Tsg101 and Nedd4.1 act successively in the assembly process of HTLV-1 to ensure proper Gag trafficking through the endocytic pathway up to late endosomes where the late steps of retroviral release occur. (PMID:15126635)
• TSG101 binds GR and protects the non-phosphorylated receptor from degradation. (PMID:15657031)
• interaction of Gag with Tsg101 and Alix favors budding from the plasma membrane and relieves a requirement for ubiquitination by Nedd4 (PMID:15908698)
• The expression and transport of ALG-2 in association with TSG101 and Vps4B are reported. (PMID:16004603)
• Data suggest that RSV and HIV-1 Gag direct particle release through independent ESCRT-mediated pathways that are linked through Tsg101-Nedd4 interaction. (PMID:16138902)
• The Tsg101 proteins function in endosomal sorting and are required to incorporate late endosomes into multivesicular bodies. (PMID:16256744)
• the ORF3 protein exploits the endosomal sorting machinery to enhance the secretion of an immunosuppressant molecule (alpha1 microglobulin) from cultured hepatocytes (PMID:16407257)
• The crystal structure of the TSG101 UEV domain (TSG101-UEV) is presented. (PMID:16552148)
• These results indicate that Tsg101 is required for the formation of stable vacuolar domains within the early endosome that develop into multivesicular body (MVBs) and Hrs is required for the accumulation of internal vesicles within MVBs. (PMID:16707569)
• Four proteins (TSG101,Hrs,Aip1/Alix, and Vps4B) of the ESCRT (endosomal sorting complex required for transport) machinery were localized in T cells and macrophages by quantitative electron microscopy. (PMID:17014699)
• analysis of mechanism of formation of the principal MDM2 isoforms, differential effects of p53 on the production of these isoforms, and differential abilities of human MDM2 isoforms as regulators of the MDM2/TSG101 and p53/MDM2 feedback control loops (PMID:17060450)
• These results demonstrate that TSG101 is important for CITED2- and HIF-1alpha-mediated cellular regulation in ovarian carcinomas. (PMID:17110434)
• role for TSG101 in the replication of EBV, a DNA virus, that differs from what is observed for RNA viruses, where TSG101 aids mainly in the endosomal sorting of enveloped late viral proteins for assembly at the plasma membrane (PMID:17182691)
• TSG101 is a specific Mahogunin substrate (PMID:17229889)
• These data suggest that an intracellular calcium store independent PKC-Sp1 signaling pathway induces early keratinocyte differentiation through upregulation of TSG101. (PMID:17321722)
• the Tsg101 protein has only weak oncogenic properties (PMID:17369844)
• ALIX can have a dramatic effect on HIV-1 release by binding at the CHMP4B site; the ability to use ALIX may allow HIV-1 to replicate in cells that express only low levels of Tsg101 (PMID:17428861)
• study shows that two proteins involved in HIV-1 budding-Tsg101, a subunit of the endosomal sorting complex required for transport I (ESCRT-I), & Alix, an ESCRT-associated protein-were recruited to the midbody during cytokinesis by interaction with Cep55 (PMID:17556548)
• TSG101 negatively regulates p21 levels, and up-regulation of TSG101 is associated with poor prognosis in ovarian cancer (PMID:17606716)
• that ALIX and TSG101/ESCRT-I also bind a series of proteins involved in cytokinesis, including CEP55, CD2AP, ROCK1, and IQGAP1. (PMID:17853893)
• Ebola virus can use vacuolar protein surting proteins independently of TSG101 for budding and reveal vacuolar sorting protein 4 as a potential target for filovirus therapeutics. (PMID:17940959)
• Tal polyubiquitinates lysine residues in the C-terminus of uncomplexed Tsg101, resulting in proteasomal degradation. (PMID:18077552)
• study found that not only the PTAP sequence in the GAT domain but also the PSAP sequence in the C-terminal region of Tom1L1 is responsible for its interaction with the UEV domain of Tsg101 and competes with the HIV-1 Gag protein for the Tsg101 interaction (PMID:18367816)
• Persistent upregulation in colorectal carcinoma cases studied. (PMID:18600204)
• Nucleocapsid region of Gag cooperates with PTAP in the recruitment of cellular proteins necessary for its L domain activity and binds the Bro1-CHMP4 complex required for LYPX(n)L-mediated budding. (PMID:19282983)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	tsg101b	ENSDARG00000011897
danio_rerio	tsg101a	ENSDARG00000040854
mus_musculus	Tsg101	ENSMUSG00000014402
rattus_norvegicus	Tsg101	ENSRNOG00000013381
drosophila_melanogaster	TSG101	FBGN0036666
caenorhabditis_elegans		WBGENE00015658

Paralogs (1): UEVLD (ENSG00000151116)

Protein

Protein identifiers

Tumor susceptibility gene 101 protein — Q99816 (reviewed: Q99816)

Alternative names: ESCRT-I complex subunit TSG101

All UniProt accessions (4): Q99816, F5H442, J3QKS4, J3QRU6

UniProt curated annotations — full annotation on UniProt →

Function. Component of the ESCRT-I complex, a regulator of vesicular trafficking process. Binds to ubiquitinated cargo proteins and is required for the sorting of endocytic ubiquitinated cargos into multivesicular bodies (MVBs). Mediates the association between the ESCRT-0 and ESCRT-I complex. Required for completion of cytokinesis; the function requires CEP55. May be involved in cell growth and differentiation. Acts as a negative growth regulator. Involved in the budding of many viruses through an interaction with viral proteins that contain a late-budding motif P-[ST]-A-P. This interaction is essential for viral particle budding of numerous retroviruses. Required for the exosomal release of SDCBP, CD63 and syndecan. It may also play a role in the extracellular release of microvesicles that differ from the exosomes.

Subunit / interactions. Component of the ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, a VPS37 protein (VPS37A to -D) and MVB12A or MVB12B in a 1:1:1:1 stoichiometry. Interacts with VPS37A, VPS37B and VPS37C. Interacts with DMAP1. Interacts with ubiquitin. Interacts with stathmin, GMCL and AATF. Component of an ESCRT-I complex (endosomal sorting complex required for transport I) which consists of TSG101, VPS28, VPS37A and UBAP1 in a 1:1:1:1 stoichiometry. Interacts with HGS; the interaction mediates the association with the ESCRT-0 complex. Interacts with GGA1 and GGA3. Interacts (via UEV domain) with PDCD6IP/AIP1. Interacts with VPS28, SNF8 and VPS36. Self-associates. Interacts with MVB12A; the association appears to be mediated by the TSG101-VPS37 binary subcomplex. Interacts with VPS37D. Interacts with LRSAM1. Interacts with CEP55; the interaction is required for cytokinesis but not for viral budding. Interacts with PDCD6. Interacts with LITAF. Interacts with MGRN1. Interacts with ARRDC1; recruits TSG101 to the plasma membrane. (Microbial infection) Interacts with HIV-1 p6. (Microbial infection) Interacts with human spumavirus Gag. (Microbial infection) Interacts with HTLV-1 Gag. (Microbial infection) Interacts with Ebola virus VP40. (Microbial infection) Interacts with EIAV p9; the interaction has been shown in vitro. (Microbial infection) Interacts with Lassa virus protein Z. (Microbial infection) Interacts with hepatitis E virus protein ORF3.

Subcellular location. Cytoplasm. Early endosome membrane. Late endosome membrane. Cytoskeleton. Microtubule organizing center. Centrosome. Midbody. Midbody ring. Nucleus.

Tissue specificity. Heart, brain, placenta, lung, liver, skeletal, kidney and pancreas.

Post-translational modifications. Monoubiquitinated at multiple sites by LRSAM1 and by MGRN1. Ubiquitination inactivates it, possibly by regulating its shuttling between an active membrane-bound protein and an inactive soluble form. Ubiquitination by MGRN1 requires the presence of UBE2D1.

Domain organisation. The UEV domain is required for the interaction of the complex with ubiquitin. It also mediates the interaction with PTAP/PSAP motifs of HIV-1 P6 protein and human spumaretrovirus Gag protein. The coiled coil domain may interact with stathmin. The UEV domain binds ubiquitin and P-[ST]-A-P peptide motif independently.

Miscellaneous. Detected in normal as well as cancer tissues.

Similarity. Belongs to the ubiquitin-conjugating enzyme family. UEV subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99816-1	1	yes
Q99816-2	2

RefSeq proteins (1): NP_006283* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008883	UEV_N	Domain
IPR016135	UBQ-conjugating_enzyme/RWD	Homologous_superfamily
IPR017916	SB_dom	Domain
IPR037202	ESCRT_assembly_dom	Homologous_superfamily
IPR052070	ESCRT-I_UEV_domain	Family

Pfam: PF05743, PF09454

UniProt features (46 total): mutagenesis site 11, strand 10, helix 8, turn 3, modified residue 2, domain 2, region of interest 2, initiator methionine 1, chain 1, splice variant 1, sequence variant 1, sequence conflict 1, coiled-coil region 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
7NLC	X-RAY DIFFRACTION	1.4
3OBQ	X-RAY DIFFRACTION	1.4
3OBS	X-RAY DIFFRACTION	1.5
3OBU	X-RAY DIFFRACTION	1.6
3OBX	X-RAY DIFFRACTION	1.6
3P9G	X-RAY DIFFRACTION	1.8
3P9H	X-RAY DIFFRACTION	1.8
1S1Q	X-RAY DIFFRACTION	2
4YC1	X-RAY DIFFRACTION	2
6VME	X-RAY DIFFRACTION	2.19
4EJE	X-RAY DIFFRACTION	2.2
7ZLX	X-RAY DIFFRACTION	2.25
2F0R	X-RAY DIFFRACTION	2.26
4ZNY	X-RAY DIFFRACTION	2.4
3IV1	X-RAY DIFFRACTION	2.5
1KPP	SOLUTION NMR
1KPQ	SOLUTION NMR
1M4P	SOLUTION NMR
1M4Q	SOLUTION NMR
5VKG	SOLUTION NMR
6UD0	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99816-F1	84.00	0.69

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 220, 2

Mutagenesis-validated functional residues (11):

Position	Phenotype
43	reduces interaction with ubiquitin; inhibits down-regulation of egfr.
45	reduces interaction with ubiquitin. no effect on mgrn1-binding.
46	reduces interaction with ubiquitin.
63	reduces interaction with hiv-1 p6; impairs hiv-1 budding.
88	reduces interaction with ubiquitin; no effect on in interaction with hiv-1 p6.
89	no change in interaction with p6; no effect on hiv-1 budding.
95	reduces interaction with vps37b and hiv-1 p6; abolishes interaction with pdcd6ip; impairs hiv-1 budding; inhibits down-r
141	reduces interaction with hiv-1 p6.
158–162	abolishes interaction with cep55 and midbody localization; no effect on interaction with escrt-i proteins, pdcd6ip and v
158–160	abolishes interaction with cep55.
368–371	loss of interaction with vps28. no effect on interaction with vps37c.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-162588	Budding and maturation of HIV virion
R-HSA-174490	Membrane binding and targetting of GAG proteins
R-HSA-917729	Endosomal Sorting Complex Required For Transport (ESCRT)
R-HSA-9610379	HCMV Late Events
R-HSA-9615710	Late endosomal microautophagy
R-HSA-9918476	Assembly and Release of Dengue Virus Virions

MSigDB gene sets: 316 (showing top): REACTOME_ENDOSOMAL_SORTING_COMPLEX_REQUIRED_FOR_TRANSPORT_ESCRT, GOBP_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PEPTIDYL_TYROSINE_PHOSPHORYLATION, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_LYSOSOMAL_TRANSPORT, GOBP_REGULATION_OF_ERBB_SIGNALING_PATHWAY, GOBP_ENDOSOME_ORGANIZATION, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_VESICLE_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_VESICLE_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_ERBB_SIGNALING_PATHWAY

GO Biological Process (28): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of cell growth (GO:0001558), extracellular transport (GO:0006858), negative regulation of epidermal growth factor-activated receptor activity (GO:0007175), negative regulation of cell population proliferation (GO:0008285), endosome to lysosome transport (GO:0008333), macroautophagy (GO:0016236), viral release from host cell (GO:0019076), keratinocyte differentiation (GO:0030216), multivesicular body assembly (GO:0036258), viral budding via host ESCRT complex (GO:0039702), negative regulation of epidermal growth factor receptor signaling pathway (GO:0042059), ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway (GO:0043162), protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway (GO:0043328), regulation of MAP kinase activity (GO:0043405), viral budding (GO:0046755), cell division (GO:0051301), regulation of cell cycle (GO:0051726), membrane fission (GO:0090148), autophagosome maturation (GO:0097352), positive regulation of exosomal secretion (GO:1903543), regulation of extracellular exosome assembly (GO:1903551), positive regulation of viral budding via host ESCRT complex (GO:1903774), exosomal secretion (GO:1990182), positive regulation of ubiquitin-dependent endocytosis (GO:2000397), protein transport (GO:0015031), cell differentiation (GO:0030154), protein modification process (GO:0036211)

GO Molecular Function (9): DNA binding (GO:0003677), transcription corepressor activity (GO:0003714), ubiquitin protein ligase binding (GO:0031625), protein homodimerization activity (GO:0042803), ubiquitin binding (GO:0043130), protein-containing complex binding (GO:0044877), virion binding (GO:0046790), calcium-dependent protein binding (GO:0048306), protein binding (GO:0005515)

GO Cellular Component (18): ESCRT I complex (GO:0000813), nucleolus (GO:0005730), cytoplasm (GO:0005737), endosome (GO:0005768), early endosome (GO:0005769), late endosome (GO:0005770), multivesicular body (GO:0005771), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), extracellular exosome (GO:0070062), Flemming body (GO:0090543), nucleus (GO:0005634), cytoskeleton (GO:0005856), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Late Phase of HIV Life Cycle	1
Synthesis And Processing Of GAG, GAGPOL Polyproteins	1
Membrane Trafficking	1
HCMV Infection	1
Autophagy	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
endosome membrane	3
endosome	3
negative regulation of DNA-templated transcription	2
viral process	2
binding	2
protein binding	2
intracellular membraneless organelle	2
late endosome	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
extracellular region	1
transport	1
epidermal growth factor receptor activity	1
negative regulation of epidermal growth factor receptor signaling pathway	1
negative regulation of protein tyrosine kinase activity	1
negative regulation of signaling receptor activity	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
lysosomal transport	1
intercellular transport	1
vesicle-mediated transport	1
autophagosome assembly	1
autophagy	1
viral life cycle	1
exit from host cell	1
epidermal cell differentiation	1
skin development	1
multivesicular body organization	1
organelle assembly	1
viral budding	1
epidermal growth factor receptor signaling pathway	1
regulation of epidermal growth factor receptor signaling pathway	1
negative regulation of ERBB signaling pathway	1
ubiquitin-dependent protein catabolic process	1
protein catabolic process in the vacuole	1

Protein interactions and networks

STRING

3008 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TSG101	VPS28	Q9UK41	999
TSG101	CD63	P08962	998
TSG101	CEP55	Q53EZ4	998
TSG101	VPS37A	Q8NEZ2	998
TSG101	PDCD6IP	Q8WUM4	997
TSG101	CD81	P18582	996
TSG101	CD9	P21926	996
TSG101	HGS	O14964	993
TSG101	ARRDC1	Q8N5I2	993
TSG101	UBAP1	Q9NZ09	986
TSG101	PDCD6	O75340	981
TSG101	MVB12A	Q96EY5	978
TSG101	VPS37B	Q9H9H4	949
TSG101	CHMP6	Q96FZ7	948
TSG101	STAM	Q92783	945

IntAct

485 interactions, top by confidence:

A	B	Type	Score
CEP55	TSG101	psi-mi:“MI:0915”(physical association)	0.970
TSG101	CEP55	psi-mi:“MI:0915”(physical association)	0.970
VPS28	TSG101	psi-mi:“MI:0915”(physical association)	0.940
TSG101	VPS28	psi-mi:“MI:0915”(physical association)	0.940
TSG101	VPS37A	psi-mi:“MI:0915”(physical association)	0.840
VPS37A	TSG101	psi-mi:“MI:0915”(physical association)	0.840
TSG101	LRSAM1	psi-mi:“MI:0915”(physical association)	0.830
LRSAM1	TSG101	psi-mi:“MI:0915”(physical association)	0.830
HGS	TSG101	psi-mi:“MI:0915”(physical association)	0.790
TSG101	VPS37C	psi-mi:“MI:0915”(physical association)	0.780
PDLIM7	TSG101	psi-mi:“MI:0915”(physical association)	0.780
VPS37C	TSG101	psi-mi:“MI:0915”(physical association)	0.780
TSG101	PDLIM7	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (593): TSG101 (Biochemical Activity), TSG101 (Co-localization), TSG101 (Co-localization), AR (Co-localization), DAPK3 (Co-localization), AATF (Co-localization), TSG101 (Two-hybrid), TSG101 (Two-hybrid), TSG101 (Two-hybrid), TAX1BP1 (Two-hybrid), PDLIM7 (Two-hybrid), MGRN1 (Two-hybrid), VPS28 (Two-hybrid), VPS37C (Two-hybrid), CEP55 (Two-hybrid)

ESM2 similar proteins: A0A8I6G705, A1L3K1, B5DFF2, B5DFI8, G3MWR8, O19048, O19137, O88508, P06730, P29338, P57721, P57722, P60335, Q12800, Q13888, Q15365, Q15366, Q16763, Q1LZ53, Q1RML1, Q28D01, Q2TBV5, Q4W5Z4, Q5E9A3, Q5FVR7, Q5NVP9, Q5TDH0, Q61990, Q6AYU1, Q6DH13, Q6P1K8, Q6ZRY4, Q7RTP6, Q8C6G8, Q8CCI5, Q8CJ19, Q8IY57, Q8N488, Q8VC52, Q921J4

Diamond homologs: A0A1F3, A5A6N7, O13276, O13277, O13278, O93401, O93537, O93538, O93539, O93540, O93541, O93542, O93543, O93544, O93545, O93546, P00336, P00337, P00338, P00339, P00340, P00341, P00342, P04642, P06151, P07195, P07864, P13490, P13491, P13743, P16125, P19629, P19858, P20373, P22988, P22989, P29038, P33571, P42119, P42120

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
LRSAM1	“down-regulates quantity”	TSG101	monoubiquitination
MGRN1	“up-regulates activity”	TSG101	monoubiquitination
TAL1	“down-regulates quantity by destabilization”	TSG101	polyubiquitination
TSG101	“form complex”	“ESCRT-I complex, VPS37A-UBAP1 variant”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 113 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Budding and maturation of HIV virion	9	47.7×	5e-11
Endosomal Sorting Complex Required For Transport (ESCRT)	9	43.1×	7e-11
Late endosomal microautophagy	8	33.9×	7e-09
HCMV Late Events	7	8.9×	1e-03
Formation of the cornified envelope	7	8.0×	2e-03
Antigen processing: Ubiquitination & Proteasome degradation	10	4.8×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	7	76.0×	6e-10
viral budding via host ESCRT complex	7	57.9×	3e-09
multivesicular body assembly	9	48.9×	7e-11
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	8	44.8×	1e-09
membrane fission	8	33.9×	9e-09
macroautophagy	8	19.9×	7e-07
morphogenesis of an epithelium	5	17.7×	6e-04
intermediate filament organization	6	14.9×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

59 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	39
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2184 predictions. Top by Δscore:

Variant	Effect	Δscore
11:18481865:TCGGC:T	acceptor_gain	1.0000
11:18481866:CGGC:C	acceptor_gain	1.0000
11:18481866:CGGCC:C	acceptor_gain	1.0000
11:18481867:GGC:G	acceptor_gain	1.0000
11:18481868:GC:G	acceptor_gain	1.0000
11:18481869:CC:C	acceptor_gain	1.0000
11:18481870:C:CC	acceptor_gain	1.0000
11:18481871:T:G	acceptor_loss	1.0000
11:18481877:C:CT	acceptor_gain	1.0000
11:18483864:A:AC	donor_gain	1.0000
11:18483865:C:CC	donor_gain	1.0000
11:18483866:TTACT:T	donor_loss	1.0000
11:18483867:TACTA:T	donor_loss	1.0000
11:18483868:A:AC	donor_gain	1.0000
11:18483868:A:C	donor_loss	1.0000
11:18483869:C:CC	donor_gain	1.0000
11:18483869:CT:C	donor_gain	1.0000
11:18483869:CTA:C	donor_gain	1.0000
11:18483869:CTACT:C	donor_gain	1.0000
11:18483874:T:TA	donor_gain	1.0000
11:18483901:T:TA	donor_gain	1.0000
11:18484068:GGGAC:G	acceptor_gain	1.0000
11:18484069:GGAC:G	acceptor_gain	1.0000
11:18484070:GAC:G	acceptor_gain	1.0000
11:18484071:AC:A	acceptor_gain	1.0000
11:18484072:CC:C	acceptor_gain	1.0000
11:18484073:C:CC	acceptor_gain	1.0000
11:18484073:CTGCA:C	acceptor_loss	1.0000
11:18484074:T:G	acceptor_loss	1.0000
11:18484076:C:CT	acceptor_gain	1.0000

AlphaMissense

2547 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:18480568:G:T	A384D	1.000
11:18480576:T:A	R381S	1.000
11:18480576:T:G	R381S	1.000
11:18480577:C:G	R381T	1.000
11:18480580:G:T	A380E	1.000
11:18480581:C:G	A380P	1.000
11:18480592:A:G	L376P	1.000
11:18480596:C:G	A375P	1.000
11:18480597:C:A	R374S	1.000
11:18480597:C:G	R374S	1.000
11:18480598:C:A	R374M	1.000
11:18480598:C:G	R374T	1.000
11:18480601:A:G	L373P	1.000
11:18480606:G:C	F371L	1.000
11:18480606:G:T	F371L	1.000
11:18480607:A:C	F371C	1.000
11:18480607:A:G	F371S	1.000
11:18480608:A:C	F371V	1.000
11:18480608:A:G	F371L	1.000
11:18480608:A:T	F371I	1.000
11:18480609:C:A	Q370H	1.000
11:18480609:C:G	Q370H	1.000
11:18480610:T:G	Q370P	1.000
11:18480616:C:G	R368P	1.000
11:18480620:A:G	S367P	1.000
11:18480622:A:G	L366P	1.000
11:18480628:C:G	R364P	1.000
11:18480629:G:T	R364S	1.000
11:18481634:A:G	L360P	1.000
11:18481634:A:T	L360Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000022417 (11:18510833 G>A), RS1000041310 (11:18481376 T>C), RS1000182665 (11:18505382 A>G), RS1000198400 (11:18498929 A>C,G), RS1000235358 (11:18517407 T>C), RS1000249254 (11:18499209 A>ATG), RS1000297433 (11:18527611 T>C), RS1000297763 (11:18498017 T>A), RS1000343029 (11:18504298 G>A), RS1000442746 (11:18491800 A>G), RS1000557000 (11:18510821 C>T), RS1000596185 (11:18485512 G>A), RS1000625311 (11:18527993 CTTTTTCTTTTTT>C), RS1000628823 (11:18485846 T>A), RS1000713480 (11:18522725 C>A)

Disease associations

OMIM: gene MIM:601387 | disease phenotypes: MIM:114480

GenCC curated gene-disease

Mondo (1): hereditary breast carcinoma (MONDO:0016419)

Orphanet (1): Hereditary breast cancer (Orphanet:227535)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C562840	Breast Cancer, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6157 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

4 potent at pChembl≥5 of 90 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.58	Ki	2600	nM	CHEMBL1946564
5.57	Ki	2700	nM	CHEMBL1946260
5.27	Ki	5400	nM	CHEMBL1946259
5.06	Ki	8700	nM	CHEMBL1946129

PubChem BioAssay actives

4 with measured affinity, of 123 total; 4 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(4S)-4-[[(2S)-2-[[(2S)-1-[(2S)-1-[(2S)-2-[[(2S,3R)-2-[[(2S,4R)-1-[(2S)-2-[[(2S)-1-acetylpyrrolidine-2-carbonyl]amino]-4-carboxybutanoyl]-4-[(E)-9H-fluoren-2-ylmethylideneamino]oxypyrrolidine-2-carbonyl]amino]-3-hydroxybutanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]-4-carboxybutanoyl]amino]-5-amino-5-oxopentanoic acid	642869: Displacement of FITC-conjugated (S)-4-((S)-1-acetylpyrrolidine-2-carboxamido)-5-((2S,4R)-2-((2S,3R)-1-((S)-1-((S)-2-((S)-2-((S)-1-((S)-1-amino-4-carboxy-1-oxobutan-2-ylamino)-4-carboxy-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)pyrrolidin-1-yl)-1-oxopropan-2-ylamino)-3-hydroxy-1-oxobutan-2-ylcarbamoyl)-4-(3,4-dimethoxybenzylideneaminooxy)pyrrolidin-1-yl)-5-oxopentanoic acid from human Tsg101 after 30 mins by Fluorescence anisotropy assay	ki	2.6000	uM
(4S)-4-[[(2S)-2-[[(2S)-1-[(2S)-1-[(2S)-2-[[(2S,3R)-2-[[(2S,4R)-1-[(2S)-2-[[(2S)-1-acetylpyrrolidine-2-carbonyl]amino]-4-carboxybutanoyl]-4-[(E)-[4-(1,3-benzodioxole-5-carbonyloxy)phenyl]methylideneamino]oxypyrrolidine-2-carbonyl]amino]-3-hydroxybutanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]-4-carboxybutanoyl]amino]-5-amino-5-oxopentanoic acid	642869: Displacement of FITC-conjugated (S)-4-((S)-1-acetylpyrrolidine-2-carboxamido)-5-((2S,4R)-2-((2S,3R)-1-((S)-1-((S)-2-((S)-2-((S)-1-((S)-1-amino-4-carboxy-1-oxobutan-2-ylamino)-4-carboxy-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)pyrrolidin-1-yl)-1-oxopropan-2-ylamino)-3-hydroxy-1-oxobutan-2-ylcarbamoyl)-4-(3,4-dimethoxybenzylideneaminooxy)pyrrolidin-1-yl)-5-oxopentanoic acid from human Tsg101 after 30 mins by Fluorescence anisotropy assay	ki	2.7000	uM
(4S)-4-[[(2S)-2-[[(2S)-1-[(2S)-1-[(2S)-2-[[(2S,3R)-2-[[(2S,4R)-1-[(2S)-2-[[(2S)-1-acetylpyrrolidine-2-carbonyl]amino]-4-carboxybutanoyl]-4-[(E)-[5-(1,3-benzothiazol-2-yl)furan-2-yl]methylideneamino]oxypyrrolidine-2-carbonyl]amino]-3-hydroxybutanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]-4-carboxybutanoyl]amino]-5-amino-5-oxopentanoic acid	642869: Displacement of FITC-conjugated (S)-4-((S)-1-acetylpyrrolidine-2-carboxamido)-5-((2S,4R)-2-((2S,3R)-1-((S)-1-((S)-2-((S)-2-((S)-1-((S)-1-amino-4-carboxy-1-oxobutan-2-ylamino)-4-carboxy-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)pyrrolidin-1-yl)-1-oxopropan-2-ylamino)-3-hydroxy-1-oxobutan-2-ylcarbamoyl)-4-(3,4-dimethoxybenzylideneaminooxy)pyrrolidin-1-yl)-5-oxopentanoic acid from human Tsg101 after 30 mins by Fluorescence anisotropy assay	ki	5.4000	uM
(4S)-4-[[(2S)-2-[[(2S)-1-[(2S)-1-[(2S)-2-[[(2S,3R)-2-[[(2S,4R)-1-[(2S)-2-[[(2S)-1-acetylpyrrolidine-2-carbonyl]amino]-4-carboxybutanoyl]-4-[(E)-(3,4-dimethoxyphenyl)methylideneamino]oxypyrrolidine-2-carbonyl]amino]-3-hydroxybutanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]-4-carboxybutanoyl]amino]-5-amino-5-oxopentanoic acid	642869: Displacement of FITC-conjugated (S)-4-((S)-1-acetylpyrrolidine-2-carboxamido)-5-((2S,4R)-2-((2S,3R)-1-((S)-1-((S)-2-((S)-2-((S)-1-((S)-1-amino-4-carboxy-1-oxobutan-2-ylamino)-4-carboxy-1-oxobutan-2-ylcarbamoyl)pyrrolidine-1-carbonyl)pyrrolidin-1-yl)-1-oxopropan-2-ylamino)-3-hydroxy-1-oxobutan-2-ylcarbamoyl)-4-(3,4-dimethoxybenzylideneaminooxy)pyrrolidin-1-yl)-5-oxopentanoic acid from human Tsg101 after 30 mins by Fluorescence anisotropy assay	ki	8.7000	uM

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases methylation, increases expression	3
Doxorubicin	affects response to substance, decreases expression	2
Particulate Matter	increases reaction, decreases expression, increases abundance, affects expression	2
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects localization, increases expression, affects cotreatment	1
arsenite	affects binding, increases reaction	1
sodium arsenite	increases expression	1
4-hydroxy-2-nonenal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
deguelin	decreases expression	1
K 7174	increases expression	1
fenpyroximate	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	affects expression, increases reaction	1
bisphenol B	increases expression	1
abrine	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
picoxystrobin	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression	1
Fulvestrant	increases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Aldosterone	affects binding, decreases reaction	1
Antimycin A	decreases expression	1
Vehicle Emissions	affects expression, increases reaction	1

ChEMBL screening assays

11 unique, capped per target: 7 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1102078	Binding	Binding affinity to ubiquitin E2 variant domain of human Tsg101 by fluorescent anisotropy	Application of ring-closing metathesis macrocyclization to the development of Tsg101-binding antagonists. — Bioorg Med Chem Lett
CHEMBL1614448	Functional	PUBCHEM_BIOASSAY: qHTS Validation Assay for Iinhibitors of HIV-1 Budding by Blocking the Interaction of PTAP/TSG101. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID485388, AID493005]	PubChem BioAssay data set

Clinical trials (associated diseases)

10 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00040222	Not specified	COMPLETED	Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Breast/Ovarian Cancer
NCT02557776	Not specified	COMPLETED	Written Genetic Counseling and Mutation Analysis of BRCA1 and BRCA2 to Patients With Breast Cancer
NCT03495544	Not specified	UNKNOWN	Study Estimating Association Between Germline Mutations and PD-L1 Expression in Breast Cancer
NCT03959267	Not specified	COMPLETED	Testing a Culturally Adapted Telephone Genetic Counseling Intervention
NCT04058418	Not specified	COMPLETED	Specialist Recommendation on FBC (Familial Breast Cancer) Chemoprevention Prescribing
NCT04125914	Not specified	ACTIVE_NOT_RECRUITING	Weight Management and Health Behavior Intervention in Lowering Cancer Risk for BRCA Positive and Lynch Syndrome Families
NCT04169542	Not specified	RECRUITING	Impact of COVID-19 Pandemic on Out-of-Pocket Costs, Lost Wages, and Unemployment in Patients With Breast Cancer Undergoing Breast Surgery
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT07292246	Not specified	RECRUITING	A Prospective CohorT Study of HandX - Assisted ENdoscopic MAstectomy: Feasibility and Safety (ATHENA I Study)
NCT07307664	Not specified	RECRUITING	Increasing Germline Genetic Testing for Patients With Cancer