TSG101, or Tumor Susceptibility Gene 101, is a fundamental component within human cells. It represents both a specific gene and its encoded protein. This protein is widely present across various cell types, playing a role in basic cellular processes. Understanding TSG101 provides insight into how cells maintain internal order and manage components.
Understanding TSG101
TSG101 refers to both the gene on human chromosome 11 and the 46-kDa protein it encodes. The protein is a component of the Endosomal Sorting Complexes Required for Transport (ESCRT) pathway, specifically ESCRT-I. While often found in the cytoplasm, TSG101 can also localize to early and late endosome membranes, the centrosome, midbody, and nucleus, depending on the cell cycle stage. These diverse locations reflect its varied functions.
TSG101’s structure includes a ubiquitin-conjugating enzyme E2 variant (UEV) domain, a proline-rich region, a coiled-coil domain, and a steadiness box. The UEV domain is notable for its ability to bind ubiquitin, a small protein tag that marks other proteins for specific cellular fates. This binding capability helps maintain cellular order by directing proteins to their appropriate destinations or for degradation.
How TSG101 Works in Cells
The primary function of the TSG101 protein is its role within the ESCRT-I complex, a heterotetramer composed of TSG101, VPS28, VPS37, and MVB12. This complex is important in protein sorting and trafficking, particularly recognizing ubiquitinated cargo. Ubiquitination is a cellular labeling system where ubiquitin molecules attach to proteins, signaling various cellular responses, including degradation or transport. TSG101’s UEV domain specifically recognizes short linear motifs, such as P(T/S)AP, found on ubiquitinated proteins.
Once TSG101 binds to ubiquitinated cargo, it helps direct these proteins into multivesicular bodies (MVBs). MVBs are specialized compartments that form by inward budding of the endosomal membrane, encapsulating proteins destined for degradation in lysosomes or for secretion as exosomes. TSG101 facilitates this inward budding and ensures correct sorting into these vesicles. The protein also mediates interactions with other ESCRT complexes, forming a coordinated pathway for cellular waste management and communication. Beyond protein sorting, TSG101 is involved in the final stage of cell division, cytokinesis, where it helps separate daughter cells. It interacts with proteins like CEP55, localizing to the midbody during cell division.
TSG101’s Role in Human Health
TSG101’s influence extends into human health, particularly concerning cancer and viral infections. Initially identified as a tumor suppressor gene in mouse fibroblasts, its role in cancer is more intricate than a simple suppressor. While its functional inactivation can lead to cellular transformation and tumor formation, its overexpression is linked to tumor progression and metastasis. For instance, mutations and alternative splicing of the TSG101 gene are frequently observed in breast cancer.
In some cancers, like colorectal carcinoma and hepatocellular carcinoma, increased TSG101 expression is associated with more aggressive tumor behavior and progression. This suggests that TSG101 can act as a tumor-promoting factor in certain cell types by regulating cell proliferation, migration, and invasion. Studies in hepatocellular carcinoma cells show that down-regulating TSG101 inhibits cell proliferation and migration, while its overexpression promotes these activities. Its complex role means TSG101 can either suppress or promote tumor development depending on the specific cancer type and cellular context.
Beyond cancer, TSG101 is a host factor that enveloped viruses, such as HIV and Ebola virus, hijack for replication. These viruses utilize TSG101 and the ESCRT pathway to facilitate their budding from infected cells. HIV’s Gag protein, for example, contains a specific “late domain” motif, PTAP, which directly binds to the UEV domain of TSG101. This interaction recruits TSG101 to the site of virus assembly on the cell membrane, allowing the virus to bud from the host cell. Disrupting this interaction can impair viral release, making TSG101 a target for antiviral strategies.
Harnessing TSG101 for Medicine
The multifaceted roles of TSG101 make it a promising target for medical advancements. Its varying expression levels in different disease states suggest its potential as a diagnostic biomarker. For instance, increased TSG101 expression has been observed in exosomes from ovarian cancer patients, indicating its potential use in early diagnosis and prognosis. Similarly, its upregulation in colorectal carcinoma and hepatocellular carcinoma tissues could serve as a biomarker for more aggressive disease.
Understanding how TSG101 functions also opens avenues for therapeutic interventions. In viral infections, developing drugs that inhibit the interaction between viral proteins and TSG101 could block viral budding. Small molecules and cyclic peptides have been identified that can interfere with the HIV Gag-TSG101 interaction, thereby inhibiting virus production without disrupting normal cellular endocytic functions. Such targeted approaches may offer advantages over traditional antiviral drugs by reducing the likelihood of viral resistance.
For cancer therapy, TSG101 inhibitors could prevent the recycling of plasma membrane receptors, often overexpressed in cancer cells, which contribute to their survival and proliferation. Preclinical studies show that TSG101 inhibitors can reduce tumor growth and enhance the effectiveness of existing chemotherapies, especially in cancers with high TSG101 levels like certain breast cancers and gliomas. Research is ongoing to elucidate its mechanisms and develop more specific and effective therapies leveraging its diverse cellular functions.