HACE1 mediated K27 ubiquitin linkage leads to YB-1 protein secretion.
Ubiquitination is an important post-translational modification that is implicated in controlling almost every biological process by targeting cellular proteins to degradation. While the importance of ubiquitination in controlling the fate and the intracellular functions of various proteins was widely studied, its role in extracellular protein secretion has been unexplored so far. In this study, by using YB-1 (Y-box Binding protein 1) as a model protein, we showed that ubiquitination is required for its extracellular secretion. We also identified HACE1 as a specific E3 ligase that polyubiquitinates YB-1 through non-canonical K27 linked ubiquitin chains. Formation of these ubiquitin linkages on YB-1 is necessary for its interaction with Tumor Susceptibility Gene 101 (TSG101), a component of the Multi-Vesicular Body (MVB) pathway, which facilitates its secretion. Finally, we demonstrated that extracellular secreted YB-1 is a functional protein that acts to inhibit Transforming Growth Factor-Beta mediated epithelial to mesenchymal transition. In summary, we identified a novel functional role for non-canonical ubiquitin linkages in mediating protein secretion.
Laboratory of Cell Death & Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad 500001, India; Graduate studies, Manipal University, Manipal 576104, India.
Vivek Reddy
VR
Palicharla
Laboratory of Cell Death & Cell Survival, Centre for DNA Fingerprinting and Diagnostics (CDFD), Nampally, Hyderabad 500001, India. Electronic address: msreddy@cdfd.org.in.
Subbareddy
S
Maddika
D045744:Cell Line, Tumor; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D057809:HEK293 Cells; D006801:Humans; D016212:Transforming Growth Factor beta / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D054875:Ubiquitination; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism*
D056827:Endosomal Sorting Complexes Required for Transport; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C497506:HACE1 protein, human; D044767:Ubiquitin-Protein Ligases
E3 ligase; Protein secretion; Ubiquitin; YB-1