1. Gene Aliases

TSG101, Tumor Susceptibility 101, VPS23, Tumor Susceptibility Gene 101 Protein, ESCRT-I Complex Subunit TSG101, Tumor Susceptibility Gene 101, Tumor Susceptibility Gene 10, TSG10, Tumor Susceptibility Protein, TSG101/CC2, CC2

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=TSG101&keywords=TSG101#aliases_descriptions]

TSG101 gene was initially identified as CC2 [PMID: 17606716, PMID: 7724523, PMID: 9482115].

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

The interactions list has been truncated to include only interactions with the strongest support from the literature.

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

Endosomal Sorting Complex Required For Transport (ESCRT): Many plasma membrane proteins are in a constant flux throughout the internal trafficking pathways of the cell. Some receptors are continuously internalized into recycling endosomes and returned to the cell surface. Others are sorted into intralumenal vesicles of morphologically distinctive endosomes that are known as multivesicular bodies (MVBs). These MVBs fuse with lysosomes, resulting in degradation of their cargo by lysosomal acidic hydrolases. Endosomes can be operationally defined as being either early or late, referring to the relative time it takes for endocytosed material to reach either stage. Ultrastructural studies indicate that early endosomes are predominantly tubulovesicular structures, which constitute a major sorting platform in the cell, whereas late endosomes show the characteristics of typical MVBs and are capable of fusing with lysosomes. A well characterized signal for shunting membrane proteins into the degradative MVB pathway is the ubiquitylation of these cargoes. At the center of a vast protein:protein and protein:lipid interaction network that underpins ubiquitin mediated sorting to the lysosome are the endosomal sorting complexes required for transport (ESCRTs), which are conserved throughout all major eukaryotic taxa.

Late endosomal microautophagy: Microautophagy (MI) is a non-selective autophagic pathway that involves internalization of cytosolic cargo through invaginations of the lysosomal membrane. MI can be induced by nitrogen starvation and complements other related self-eating processes such as Macroautophagy (MA) and Chaperone Mediated Autophagy (CMA). MI can degrade cell organelles and bulk cytosolic proteins directly via the lysosome and late endosome. MI can also target substrates with KFERQ motifs with the help of HSPA8 (Li W W et al. 2012).

Budding and maturation of HIV virion: With the virus components precariously assembled on the inner leaflet of the plasma membrane, the host cell machinery is required for viral budding. The virus takes advantage of the host ESCRT pathway to terminate Gag polymerization and catalyze release. The ESCRT pathway is normally responsible for membrane fission that creates cytoplasm filled vesicular bodies. In this case HIV (and other viruses) take advantage of the ESCRT cellular machinery to facilitate virion budding from the host.

Membrane binding and targeting of GAG proteins: One of the mysteries of Gag protein involvement in HIV virion assembly is how the proteins are targeted to the proper membrane for budding. Infectious retroviruses do not bud from all of the available membrane surfaces within an infected cell, but primarily from the plasma membrane, which constitutes a small proportion of the total membrane surface in most cells. In polarized cells, the sites of budding are further restricted to the basolateral membrane.

HCMV Late Events: Once Human Cytomegalovirus (HCMV) Immediate Early (IE) and Delayed Early (DE) gene products begin to appear the processes driving DNA replication, Late (L) gene expression, and virion assembly begin.

GO terms:

cell differentiation [The cellular developmental process in which a relatively unspecialized cell, e.g. embryonic or regenerative cell, acquires specialized structural and/or functional features that characterize a specific cell. Differentiation includes the processes involved in commitment of a cell to a specific fate and its subsequent development to the mature state. GO:0030154]

cell division [The process resulting in division and partitioning of components of a cell to form more cells; may or may not be accompanied by the physical separation of a cell into distinct, individually membrane-bounded daughter cells.|Note that this term differs from 'cytokinesis ; GO:0000910' in that cytokinesis does not include nuclear division. GO:0051301]

endosome to lysosome transport [The directed movement of substances from endosomes to lysosomes. GO:0008333]

exosomal secretion [The process whereby a membrane-bounded vesicle is released into the extracellular region by fusion of the limiting endosomal membrane of a multivesicular body with the plasma membrane. GO:1990182]

extracellular transport [The transport of substances that occurs outside cells. GO:0006858]

keratinocyte differentiation [The process in which a relatively unspecialized cell acquires specialized features of a keratinocyte. GO:0030216]

negative regulation of cell population proliferation [Any process that stops, prevents or reduces the rate or extent of cell proliferation. GO:0008285]

negative regulation of epidermal growth factor receptor signaling pathway [Any process that stops, prevents, or reduces the frequency, rate or extent of epidermal growth factor receptor signaling pathway activity. GO:0042059]

negative regulation of transcription by RNA polymerase II [Any process that stops, prevents, or reduces the frequency, rate or extent of transcription mediated by RNA polymerase II. GO:0000122]

positive regulation of DNA-templated transcription [Any process that activates or increases the frequency, rate or extent of cellular DNA-templated transcription. GO:0045893]

positive regulation of exosomal secretion [Any process that activates or increases the frequency, rate or extent of exosomal secretion. GO:1903543]

positive regulation of ubiquitin-dependent endocytosis [Any process that activates or increases the frequency, rate or extent of ubiquitin-dependent endocytosis. GO:2000397]

positive regulation of viral budding via host ESCRT complex [Any process that activates or increases the frequency, rate or extent of viral budding via host ESCRT complex. GO:1903774]

protein modification process [The covalent alteration of one or more amino acids occurring in proteins, peptides and nascent polypeptides (co-translational, post-translational modifications). Includes the modification of charged tRNAs that are destined to occur in a protein (pre-translation modification). GO:0036211]

protein monoubiquitination [Addition of a single ubiquitin group to a protein. GO:0006513]

protein transport [The directed movement of proteins into, out of or within a cell, or between cells, by means of some agent such as a transporter or pore. GO:0015031]

regulation of cell cycle [Any process that modulates the rate or extent of progression through the cell cycle. GO:0051726]

regulation of cell growth [Any process that modulates the frequency, rate, extent or direction of cell growth. GO:0001558]

regulation of extracellular exosome assembly [Any process that modulates the frequency, rate or extent of extracellular vesicular exosome assembly. GO:1903551]

ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway [The chemical reactions and pathways resulting in the breakdown of a protein or peptide covalently tagged with ubiquitin, via the multivesicular body (MVB) sorting pathway; ubiquitin-tagged proteins are sorted into MVBs, and delivered to a lysosome/vacuole for degradation. GO:0043162]

viral budding [A viral process by which enveloped viruses acquire a host-derived membrane enriched in viral proteins to form their external envelope. The process starts when nucleocapsids, assembled or in the process of being built, induce formation of a membrane curvature in the host plasma or organelle membrane and wrap up in the forming bud. The process ends when the bud is eventually pinched off by membrane scission to release the enveloped particle into the lumenal or extracellular space. GO:0046755]

viral release from host cell [The dissemination of mature viral particles from a host cell, e.g. by cell lysis or the budding of virus particles from the cell membrane. GO:0019076]

MSigDB Signatures:

BLALOCK_ALZHEIMERS_DISEASE_DN: Genes down-regulated in brain from patients with Alzheimer's disease.

KIM_BIPOLAR_DISORDER_OLIGODENDROCYTE_DENSITY_CORR_UP: Genes whose expression significantly and positively correlated with oligodendrocyte density in layer VI of BA9 brain region in patients with bipolar disorder.

REACTOME_AUTOPHAGY: Autophagy

REACTOME_MEMBRANE_TRAFFICKING: Membrane Trafficking

REACTOME_INFECTIOUS_DISEASE: Infectious disease

REACTOME_HIV_INFECTION: HIV Infection

KEGG_ENDOCYTOSIS: Endocytosis

PID_REG_GR_PATHWAY: Glucocorticoid receptor regulatory network

PID_ERBB1_INTERNALIZATION_PATHWAY: Internalization of ErbB1

WHITFIELD_CELL_CYCLE_G2_M: Genes periodically expressed in synchronized HeLa cells (cervical carcinoma), with peak during the G2/M phase of cell cycle.

BENPORATH_CYCLING_GENES: Genes showing cell-cycle stage-specific expression [PMID: 12058064].

REACTOME_ASSEMBLY_OF_THE_HIV_VIRION: Assembly Of The HIV Virion

REACTOME_ENDOSOMAL_SORTING_COMPLEX_REQUIRED_FOR_TRANSPORT_ESCRT: Endosomal Sorting Complex Required For Transport (ESCRT)

REACTOME_VIRAL_INFECTION_PATHWAYS: Viral Infection Pathways

REACTOME_HCMV_INFECTION: HCMV Infection

REACTOME_BUDDING_AND_MATURATION_OF_HIV_VIRION: Budding and maturation of HIV virion

REACTOME_LATE_ENDOSOMAL_MICROAUTOPHAGY: Late endosomal microautophagy

REACTOME_HIV_LIFE_CYCLE: HIV Life Cycle

ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_UP: Genes up-regulated in liver tumor compared to the normal adjacent tissue.

WP_7Q11_23_COPY_NUMBER_VARIATION_SYNDROME: 7q11 23 copy number variation syndrome

REACTOME_VESICLE_MEDIATED_TRANSPORT: Vesicle-mediated transport

REACTOME_HCMV_LATE_EVENTS: HCMV Late Events

7. Gene Descriptions

NCBI Gene Summary: 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.

GeneCards Summary: TSG101 (Tumor Susceptibility 101) is a Protein Coding gene. Diseases associated with TSG101 include Hepatitis E and Charcot-Marie-Tooth Disease, Axonal, Type 2P. Among its related pathways are Budding and maturation of HIV virion and HIV Life Cycle. Gene Ontology (GO) annotations related to this gene include protein homodimerization activity and transcription corepressor activity. An important paralog of this gene is UEVLD.

UniProtKB/Swiss-Prot Summary: 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 [PMID: 22660413]. It may also play a role in the extracellular release of microvesicles that differ from the exosomes [PMID: 22315426].

8. Cellular Location of Gene Product

General cytoplasmic and membranous expression. Mainly localized to the cytosol. In addition localized to the nucleoli & plasma membrane. Predicted location: Intracellular [https://www.proteinatlas.org/ENSG00000074319/subcellular]

9. Mechanistic Information

Summary

TSG101 is a protein that is part of the ESCRT-I complex, crucial in sorting ubiquitinated cargo into multivesicular bodies (MVBs) and facilitating cytokinesis [CS: 10]. It is associated with cell growth regulation, and the exosomal secretion of proteins important in neuroregenerative processes [CS: 8]. In response to brain toxicity, such as hypoxic or ischemic conditions, TSG101 expression is upregulated to augment the production of exosomes, which are instrumental in clearing damaged cellular contents and reducing inflammation [CS: 7]. This upregulation might facilitate the protective response of neurons to stress by promoting the secretion of exosomes that can deliver neuroprotective substances to distressed cells, thereby contributing to the mitigation of damage and aiding in the preservation of neuronal function [CS: 6].

In the context of brain disease, an upregulation of TSG101 expression has been documented in glioma tissue, where increased levels correlate with enhanced proliferation, migration, and invasion of these cancer cells [CS: 9]. The mechanism behind this involves TSG101's modulation of the AKT/GSK3beta/beta-catenin [CS: 8] and RhoC/Cofilin signaling pathways [CS: 7], integral to cell growth and the cytoskeletal rearrangements needed for cell movement. Therefore, in the event of glioma, TSG101 upregulation is an adaptive response that facilitates the aberrant proliferation and spread of tumor cells, highlighting its role in cell cycle regulation and signaling [CS: 8].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: low tissue specificity [https://www.proteinatlas.org/ENSG00000074319/tissue]

Cell type enchanced: oocytes, syncytiotrophoblasts (cell type enhanced) [https://www.proteinatlas.org/ENSG00000074319/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

Compounds that decrease expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

Most relevant biomarkers with lower score or lower probability of association with disease or organ of interest: