TSG101

TSG101
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1KPP, 1KPQ, 1M4P, 1M4Q, 1S1Q, 2F0R, 3IV1, 3OBQ, 3OBS, 3OBU, 3OBX, 3P9G, 3P9H, 4EJE, 4YC1, 4ZNY
Identifiers
Aliases	TSG101 , TSG10, VPS23, tumor susceptibility 101
External IDs	OMIM: 601387; MGI: 106581; HomoloGene: 4584; GeneCards: TSG101; OMA:TSG101 - orthologs
Gene location (Human) Chr. Chromosome 11 (human) [1] Band 11p15.1 Start 18,468,336 bp [1] End 18,526,951 bp [1]
Gene location (Mouse) Chr. Chromosome 7 (mouse) [2] Band 7|7 B3 Start 46,538,697 bp [2] End 46,569,717 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in oocyte secondary oocyte gonad ganglionic eminence islet of Langerhans amniotic fluid gingival epithelium gastrocnemius muscle rectum parotid gland Top expressed in tail of embryo ganglionic eminence ventricular zone genital tubercle maxillary prominence mandibular prominence neural tube medial ganglionic eminence neural layer of retina muscle of thigh More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding protein homodimerization activity transcription corepressor activity calcium-dependent protein binding ubiquitin binding protein binding nuclear receptor coactivator activity virion binding ubiquitin protein ligase binding protein-containing complex binding Cellular component cytoplasm multivesicular body endosome late endosome membrane late endosome membrane plasma membrane early endosome nucleolus endosome membrane extracellular exosome ESCRT I complex nucleus cytosol host cell microtubule organizing center cytoskeleton early endosome membrane Flemming body Biological process intracellular transport of virus cell differentiation positive regulation of ubiquitin-dependent endocytosis regulation of extracellular exosome assembly viral budding via host ESCRT complex viral life cycle endosome to lysosome transport multivesicular body assembly protein monoubiquitination viral budding keratinocyte differentiation cell division endosomal transport autophagosome maturation regulation of cell growth protein transport ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway regulation of MAP kinase activity positive regulation of exosomal secretion cell cycle regulation of growth negative regulation of transcription, DNA-templated negative regulation of cell population proliferation viral process exosomal secretion macroautophagy negative regulation of epidermal growth factor receptor signaling pathway negative regulation of epidermal growth factor-activated receptor activity transport extracellular transport positive regulation of nucleic acid-templated transcription Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7251 22088 Ensembl ENSG00000074319 ENSMUSG00000014402 UniProt Q99816 Q61187 RefSeq (mRNA) NM_006292 NM_021884 NM_001348088 NM_001348089 RefSeq (protein) NP_006283 NP_068684 NP_001335017 NP_001335018 Location (UCSC) Chr 11: 18.47 – 18.53 Mb Chr 7: 46.54 – 46.57 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Tumor susceptibility gene 101, also known as TSG101, is a human gene that encodes for a cellular protein of the same name.

Function

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. ^[5]

The main role of TSG101 is to participate in ESCRT pathway. This pathway facilitates reverse topology budding and formation of multivesicular bodies (MVB) which delivers cargo destined for degradation to the lysosomes. ^[6] TSG101 recognises short linear motif  : P(T/S)AP via the UEV protein domain of the VPS23/TSG101 subunit. The assembly of the ESCRT-I complex is directed by the C-terminal steadiness box (SB) of VPS23, the N-terminal half of VPS28, and the C-terminal half of VPS37. The structure is primarily composed of three long, parallel helical hairpins, each corresponding to a different subunit. The additional domains and motifs extending beyond the core serve as gripping tools for ESCRT-I critical functions. ^{[7] [8]}

Viral Hijacking

TSG101 plays an important role in the pathogenesis of HIV and other viruses. In uninfected cells, TSG101 functions in the biogenesis of the multivesicular body (MVB), ^[9] which suggests that HIV may bind TSG101 in order to gain access to the downstream machinery that catalyzes MVB vesicle budding. ^[10]

Interactions

TSG101 has been shown to interact with:

• EP300, ^[11]
• HGS, ^{[12] [13]}
• LRSAM1, ^{[12] [14]}
• P21, ^[15]
• P53, ^[16] and
• VPS28. ^{[12] [17] [18]}

Orthologue, Vps23

Vps23_core
escrt-i core
Identifiers
Symbol	Vps23_core
Pfam	PF09454
InterPro	IPR017916
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

In humans, the orthologue of vps23 which has a component of ESCRT-1 is called Tsg101. Mutations in Tsg-101 have been linked to cervical, breast, prostate and gastrointestinal cancers. In molecular biology, vps23 (vacuolar protein sorting) is a protein domain. Vps proteins are components of the ESCRTs (endosomal sorting complexes required for transport) which are required for protein sorting at the early endosome. More specifically, vps23 is a component of ESCRT-I. The ESCRT complexes form the machinery driving protein sorting from endosomes to lysosomes. ESCRT complexes are central to receptor down-regulation, lysosome biogenesis and budding of HIV.

Structure

Yeast ESCRT-I consists of three protein subunits, VPS23, VPS28, and VPS37. In humans, ESCRT-I comprises TSG101, VPS28, and one of four potential human VPS37 homologues.

See also

• FGI-104 - an ESCRT inhibitor being researched as a broad spectrum antiviral

References

1. GRCh38: Ensembl release 89: ENSG00000074319 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000014402 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: TSG101 tumor susceptibility gene 101".
6. Henne WM, Buchkovich NJ, Emr SD (July 2011). "The ESCRT pathway". Developmental Cell. 21 (1): 77–91. doi: 10.1016/j.devcel.2011.05.015 . PMID   21763610.
7. Teo H, Gill DJ, Sun J, Perisic O, Veprintsev DB, Vallis Y, Emr SD, Williams RL (April 2006). "ESCRT-I core and ESCRT-II GLUE domain structures reveal role for GLUE in linking to ESCRT-I and membranes". Cell. 125 (1): 99–111. doi: 10.1016/j.cell.2006.01.047 . PMID   16615893. S2CID   14017291.
8. Kostelansky MS, Sun J, Lee S, Kim J, Ghirlando R, Hierro A, Emr SD, Hurley JH (April 2006). "Structural and functional organization of the ESCRT-I trafficking complex". Cell. 125 (1): 113–26. doi:10.1016/j.cell.2006.01.049. PMC   1576341 . PMID   16615894.
9. Katzmann DJ, Odorizzi G, Emr SD (2002). "Receptor downregulation and multivesicular-body sorting". Nat. Rev. Mol. Cell Biol. 3 (12): 893–905. doi:10.1038/nrm973. PMID   12461556. S2CID   1344520.
10. von Schwedler UK, Stuchell M, Müller B, Ward DM, Chung HY, Morita E, Wang HE, Davis T, He GP, Cimbora DM, Scott A, Kräusslich HG, Kaplan J, Morham SG, Sundquist WI (2003). "The protein network of HIV budding". Cell. 114 (6): 701–13. doi: 10.1016/S0092-8674(03)00714-1 . PMID   14505570. S2CID   16894972.
11. Sun Z, Pan J, Hope WX, Cohen SN, Balk SP (August 1999). "Tumor susceptibility gene 101 protein represses androgen receptor transactivation and interacts with p300". Cancer. 86 (4): 689–96. doi: 10.1002/(sici)1097-0142(19990815)86:4<689::aid-cncr19>3.0.co;2-p . PMID   10440698. S2CID   26971556.
12. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID   16189514. S2CID   4427026.
13. Lu Q, Hope LW, Brasch M, Reinhard C, Cohen SN (June 2003). "TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation". Proc. Natl. Acad. Sci. U.S.A. 100 (13): 7626–31. Bibcode:2003PNAS..100.7626L. doi: 10.1073/pnas.0932599100 . PMC   164637 . PMID   12802020.
14. Amit I, Yakir L, Katz M, Zwang Y, Marmor MD, Citri A, Shtiegman K, Alroy I, Tuvia S, Reiss Y, Roubini E, Cohen M, Wides R, Bacharach E, Schubert U, Yarden Y (July 2004). "Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding". Genes Dev. 18 (14): 1737–52. doi:10.1101/gad.294904. PMC   478194 . PMID   15256501.
15. Oh H, Mammucari C, Nenci A, Cabodi S, Cohen SN, Dotto GP (April 2002). "Negative regulation of cell growth and differentiation by TSG101 through association with p21(Cip1/WAF1)". Proc. Natl. Acad. Sci. U.S.A. 99 (8): 5430–5. Bibcode:2002PNAS...99.5430O. doi: 10.1073/pnas.082123999 . PMC   122786 . PMID   11943869.
16. Li L, Liao J, Ruland J, Mak TW, Cohen SN (February 2001). "A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control". Proc. Natl. Acad. Sci. U.S.A. 98 (4): 1619–24. Bibcode:2001PNAS...98.1619L. doi: 10.1073/pnas.98.4.1619 . PMC   29306 . PMID   11172000.
17. Stuchell MD, Garrus JE, Müller B, Stray KM, Ghaffarian S, McKinnon R, Kräusslich HG, Morham SG, Sundquist WI (August 2004). "The human endosomal sorting complex required for transport (ESCRT-I) and its role in HIV-1 budding". J. Biol. Chem. 279 (34): 36059–71. doi: 10.1074/jbc.M405226200 . PMID   15218037.
18. Bishop N, Woodman P (April 2001). "TSG101/mammalian VPS23 and mammalian VPS28 interact directly and are recruited to VPS4-induced endosomes". J. Biol. Chem. 276 (15): 11735–42. doi: 10.1074/jbc.M009863200 . PMID   11134028.

Further reading

• Mazzé FM, Degrève L (2006). "The role of viral and cellular proteins in the budding of human immunodeficiency virus". Acta Virol. 50 (2): 75–85. PMID   16808324.
• Freed EO, Mouland AJ (2006). "The cell biology of HIV-1 and other retroviruses". Retrovirology. 3: 77. doi: 10.1186/1742-4690-3-77 . PMC   1635732 . PMID   17083721.
• Koonin EV, Abagyan RA (1997). "TSG101 may be the prototype of a class of dominant negative ubiquitin regulators". Nat. Genet. 16 (4): 330–1. doi:10.1038/ng0897-330. PMID   9241264. S2CID   36275138.
• Steiner P, Barnes DM, Harris WH, Weinberg RA (1997). "Absence of rearrangements in the tumour susceptibility gene TSG101 in human breast cancer". Nat. Genet. 16 (4): 332–3. doi:10.1038/ng0897-332. PMID   9241265. S2CID   20233125.
• Lee MP, Feinberg AP (1997). "Aberrant splicing but not mutations of TSG101 in human breast cancer". Cancer Res. 57 (15): 3131–4. PMID   9242438.
• Gayther SA, Barski P, Batley SJ, Li L, de Foy KA, Cohen SN, Ponder BA, Caldas C (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. 15 (17): 2119–26. doi:10.1038/sj.onc.1201591. PMID   9366528. S2CID   7819803.
• Xie W, Li L, Cohen SN (1998). "Cell cycle-dependent subcellular localization of the TSG101 protein and mitotic and nuclear abnormalities associated with TSG101 deficiency". Proc. Natl. Acad. Sci. U.S.A. 95 (4): 1595–600. Bibcode:1998PNAS...95.1595X. doi: 10.1073/pnas.95.4.1595 . PMC   19109 . PMID   9465061.
• Wagner KU, Dierisseau P, Rucker EB, Robinson GW, Hennighausen L (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. 17 (21): 2761–70. doi:10.1038/sj.onc.1202529. PMID   9840940. S2CID   29505462.
• Sun Z, Pan J, Hope WX, Cohen SN, Balk SP (1999). "Tumor susceptibility gene 101 protein represses androgen receptor transactivation and interacts with p300". Cancer. 86 (4): 689–96. doi: 10.1002/(SICI)1097-0142(19990815)86:4<689::AID-CNCR19>3.0.CO;2-P . PMID   10440698. S2CID   26971556.
• Hittelman AB, Burakov D, Iñiguez-Lluhí JA, Freedman LP, Garabedian MJ (1999). "Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins". EMBO J. 18 (19): 5380–8. doi:10.1093/emboj/18.19.5380. PMC   1171607 . PMID   10508170.
• Rountree MR, Bachman KE, Baylin SB (2000). "DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci". Nat. Genet. 25 (3): 269–77. doi:10.1038/77023. PMID   10888872. S2CID   26149386.
• Bishop N, Woodman P (2001). "TSG101/mammalian VPS23 and mammalian VPS28 interact directly and are recruited to VPS4-induced endosomes". J. Biol. Chem. 276 (15): 11735–42. doi: 10.1074/jbc.M009863200 . PMID   11134028.
• Li L, Liao J, Ruland J, Mak TW, Cohen SN (2001). "A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control". Proc. Natl. Acad. Sci. U.S.A. 98 (4): 1619–24. Bibcode:2001PNAS...98.1619L. doi: 10.1073/pnas.98.4.1619 . PMC   29306 . PMID   11172000.
• VerPlank L, Bouamr F, LaGrassa TJ, Agresta B, Kikonyogo A, Leis J, Carter CA (2001). "Tsg101, a homologue of ubiquitin-conjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55(Gag)". Proc. Natl. Acad. Sci. U.S.A. 98 (14): 7724–9. Bibcode:2001PNAS...98.7724V. doi: 10.1073/pnas.131059198 . PMC   35409 . PMID   11427703.
• Garrus JE, von Schwedler UK, Pornillos OW, Morham SG, Zavitz KH, Wang HE, Wettstein DA, Stray KM, Côté M, Rich RL, Myszka DG, Sundquist WI (2001). "Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding". Cell. 107 (1): 55–65. doi: 10.1016/S0092-8674(01)00506-2 . PMID   11595185. S2CID   18525780.
• Martin-Serrano J, Zang T, Bieniasz PD (2002). "HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress". Nat. Med. 7 (12): 1313–9. doi:10.1038/nm1201-1313. PMID   11726971. S2CID   19655035.
• Demirov DG, Ono A, Orenstein JM, Freed EO (2002). "Overexpression of the N-terminal domain of TSG101 inhibits HIV-1 budding by blocking late domain function". Proc. Natl. Acad. Sci. U.S.A. 99 (2): 955–60. Bibcode:2002PNAS...99..955D. doi: 10.1073/pnas.032511899 . PMC   117412 . PMID   11805336.
• Bennett NA, Pattillo RA, Lin RS, Hsieh CY, Murphy T, Lyn D (2002). "TSG101 expression in gynecological tumors: relationship to cyclin D1, cyclin E, p53 and p16 proteins". Cell. Mol. Biol. (Noisy-le-grand). 47 (7): 1187–93. PMID   11838966.
• Bishop N, Horman A, Woodman P (2002). "Mammalian class E vps proteins recognize ubiquitin and act in the removal of endosomal protein-ubiquitin conjugates". J. Cell Biol. 157 (1): 91–101. doi:10.1083/jcb.200112080. PMC   2173266 . PMID   11916981.