Tumor susceptibility 101 protein (human TSG101 theoretical molecular weight 44kDa) is the mammalian homologue of the yeast protein Vps23 which plays a role in endosomal and multivesicular body trafficking. TSG101 forms part of the endosomal sorting complexes required for transport complex 1 (ESCRT-I), a cytosolic multiprotein complex consisting additionally of Vps28, Vps37 (A-D) and Mvb12 (A, B) or UBAP1 (1). TSG101 contains multiple domains including the amino terminal ubiquitin e2 variant (UEV) domain, a proline-rich (RRR) domain, a coiled coil (CC) domain, and a carboxy terminal alpha-helical/steadiness box (SB) domain (2). As part of the ESCRT-I complex, TSG101 interacts through its UEV domain with ubiquitinated membrane proteins and members of the ESCRT-0 complex. The UEV domain plays a critical role for various TSG101 functions such as protein sorting into multivesicular bodies and late endosomes, and in the process of viral budding. For example, TSG101 interacts with the intermediate-conductance, Ca2+ -activated K+ channel (KCa3.1), facilitating its targeting to the lysosome for degradation (3). Additionally, TSG101 has been implicated in the turnover of connexins such as connexins 43 and 45 (4). TSG101 plays a role in other cellular functions including transcriptional regulation, cytokinesis and cell growth (2).
Upon its initial discovery, TSG101 was recognized as a tumor suppressor protein due to the identification of deletions within the TSG101 gene in human breast carcinomas. However, re-examination of the initial findings argued against this function and supported that TSG101 promotes tumorigenesis (2). In agreement with this role, TSG101 expression is upregulated in several types of cancer including breast, ovarian, and colorectal carcinoma.
1. Schmidt, O., & Teis, D. (2012). The ESCRT machinery. Current Biology. https://doi.org/10.1016/j.cub.2012.01.028
2. Jiang, Y., Ou, Y., & Cheng, X. (2013). Role of TSG101 in cancer. Frontiers in Bioscience. https://doi.org/10.2741/4099
3. Balut, C. M., Gao, Y., Murray, S. A., Thibodeau, P. H., & Devor, D. C. (2010). ESCRT-dependent targeting of plasma membrane localized KCa3.1 to the lysosomes. American Journal of Physiology - Cell Physiology. https://doi.org/10.1152/ajpcell.00120.2010
4. Su, V., & Lau, A. F. (2014). Connexins: Mechanisms regulating protein levels and intercellular communication. FEBS Letters. https://doi.org/10.1016/j.febslet.2014.01.013