Mammalian Tumor Susceptibility Gene 101 (TSG101) and the Yeast Homologue, Vps23p, Both Function in Late Endosomal Trafficking

Abstract

The mammalian tumor susceptibility gene tsg101 encodes the homologue of Vps23p, a class E Vps protein essential for normal membrane trafficking in the late endosome/multivesicular body of yeast. Both proteins assemble into large ( 350 kDa) cytosolic protein complexes and we show that the yeast complex contains another class E Vps protein, Vps28p. tsg101 mutant cells exhibit defects in sorting and proteolytic maturation of the lysosomal hydrolase cathepsin D, as well as in the steady-state distribution of the mannose-6-phosphate receptor. Additionally, endocytosed EGF receptors that are normally sorted to the lysosome are instead rapidly recycled back to the cell surface in tsg101 mutant cells. We propose that tsg101 mutant cells are defective in the delivery of cargo proteins to late endosomal compartments. One consequence of this endosomal trafficking defect is the delayed down-regulation/degradation of activated cell surface receptors, resulting in prolonged signaling. This may contribute to the tumorigenic phenotype exhibited by the tsg101 mutant fibroblasts.

Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding

“…5G). Notably, a similar behavior of MAPK signaling was observed in cells defective in Tsg101 (Babst et al 2000), in line with the proposition that Tal inactivates Tsg101 by means of multiubiquitylation.…”

“…Normal internalization of EGFRs was observed in fibroblasts depleted of Tsg101, but instead of trafficking to lysosomes, EGFRs were shunted in a late endocytic compartment to a recycling pathway (Babst et al 2000). In line with lack of involvement in early steps of endocytosis, overexpression of hTal did not alter the rapid translocation of a fluorescent derivative of EGF to endocytic vesicles (Fig.…”

“…Mammalian and yeast Tsg101/ Vps23p assemble into a large complex, termed ESCRT-1, which recognizes ubiquitylated cargo originating from either the Golgi apparatus or the plasma membrane, and sorts them into the vacuolar/lysosomal lumen (Katzmann et al 2001). Accordingly, reduced expression of Tsg101 shunts active EGFRs from the normal degradative pathway to a recycling route (Babst et al 2000). Hence, like oncogenic forms of Cbl, aberrant expression of Tsg101 may transform cells by enhancing growth factor signaling.…”

ROCK I-mediated activation of NF-κB by RhoB

“…In a recent study we have determined that Bcr interacts with TSG101, and is also a subunit of the mammalian sorting complex [25,26]. Although the precise role that RhoB plays in this sorting pathway is unclear, it has also been localized to the MVB, and interference with RhoB, Bcr or TSG101 have an equivalent phenotype with regard to receptor turnover [5,25,52]. Although RhoB has not been shown to directly interact with TSG101 or Bcr, Bcr contains a Rho-specific guanine nucleotide exchange factor activity, and thus, may utilize endogenous RhoB as a substrate for NF-κB activation.…”

ESCRT-I Component VPS23A Affects ABA Signaling by Recognizing ABA Receptors for Endosomal Degradation

“…Both yeast Vps23p and human TSG101 are required for the efficient trafficking and degradation of misfolded cell-surface receptors (Babst et al, 2000). Vps23p, which has been identified as one of the suppressors of temperature-sensitive α-factor receptor (mutation ste2-3) and arginine permease (mutation can1 ts ), plays no obvious role in cell division, whereas human TSG101 has been implicated in several biological processes, including cytokinesis, cell cycling and proliferation, protein ubiquitination, transcriptional regulation, and viral budding (Jiang et al, 2013;Li et al, 1999).…”