Tsg101

TSG101, or tumor susceptibility gene 101, encodes a protein that is a core component of the ESCRT-I complex, a key machinery in endosomal sorting and multivesicular body formation. The protein is conserved across eukaryotes and shares homology with yeast Vps23. In humans, TSG101 interacts with other ESCRT-I members such as VPS28 and VPS37 and with ubiquitinated cargo destined for lysosomal degradation.

Functionally, TSG101 participates in the recognition and sorting of ubiquitinated membrane proteins into intraluminal vesicles of multivesicular bodies, contributing to receptor downregulation and protein turnover. It also participates in additional membrane trafficking steps linked to endosome-to-lysosome pathways and may influence cytokinetic abscission through ESCRT-mediated membrane remodeling. The N-terminal ubiquitin-conjugating enzyme–like (UEV) domain of TSG101 binds to ubiquitin and to PTAP-containing motifs found in certain cargo or viral proteins, enabling interactions that drive vesicular trafficking. The UEV domain lacks catalytic activity but mediates essential protein–protein interactions.

Clinical and research relevance: TSG101 was identified as a potential tumor suppressor in mouse models, but in humans its role is not that of a classical tumor suppressor, and the gene is considered essential for viability. Abnormal expression has been observed in various cancers, though the relationship to oncogenesis is complex. In virology, TSG101 is a host factor exploited by several enveloped viruses; for example, the HIV-1 Gag p6 late domain recruits TSG101 to promote budding and particle release.

Overall, TSG101 is a multifunctional, evolutionarily conserved protein central to ESCRT-I–mediated trafficking, with additional implications in viral replication and cellular viability.