Tumor Suppressor Gene 101: A Virus’ Multifunctional Conduit to the ESCRT Trafficking Machinery

Abstract Eukaryotic cells transport proteins and lipids between the exterior and interior environments using membrane-bounded vesicles that travel by two major pathways: the outward, exocytic pathway, and the inward, endocytic pathway. The product of the tumor suppressor gene 101 (Tsg101) is a highly conserved protein and component of the e ndosomal s orting c omplex r equired for t ransport (ESCRT) machinery whose function is exploited by viruses that utilize both pathways. Tsg101's critical function is to recognize and sort the ESCRT cargo. While the ESCRT machinery is best known for its role in trafficking of cellular cargo from the plasma membrane to degradative compartments in the cell interior, viruses use it to facilitate egress from the cell periphery. This chapter focuses on the unique molecular properties of Tsg101 that enable it to be exploited by pathogens to gain access to the machinery's membrane remodeling apparatus necessary for their separation from the host. Particular emphasis is placed on how the structure of Tsg101 contributes to its unique role as an assembly chaperone to the retrovirus HIV-1, permitting the virus to influence ESCRT machinery interaction with other cellular machineries, including phosphatidylinositol lipid and calcium signaling systems. The role of Tsg101 in the egress of viruses outside the Retroviridae and its potential as a target for broadly effective antiviral drug development also is discussed. Although many questions remain, our understanding is growing of the Tsg101 protein and the complex mechanism by which it facilitates the virus budding process, just one of its many functions.