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Published on: March 26, 2014
TRIM11 activates the proteasome and promotes overall protein degradation by regulating USP14
Liang Chen1, Guixin Zhu1, Eleanor M Johns1
1Department of Cancer Biology and Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Abstract:
The proteasome is a complex protease critical for protein quality control and cell regulation, and its dysfunction is associated with cancer and other diseases. However, the mechanisms that control proteasome activity in normal and malignant cells remain unclear. Here we report that TRIM11 enhances degradation of aberrant and normal regulatory proteins, and augments overall rate of proteolysis. Mechanistically, TRIM11 binds to both the proteasome and USP14, a deubiquitinase that prematurely removes ubiquitins from proteasome-bound substrates and also noncatalytically inhibits the proteasome, and precludes their association, thereby increasing proteasome activity. TRIM11 promotes cell survival and is upregulated upon heat shock. Moreover, TRIM11 is required for tumor growth, and increased expression of TRIM11 correlates with poor clinical survival. These findings identify TRIM11 as an important activator of the proteasome, define a pathway that adjusts proteasome activity, and reveal a mechanism by which tumor cells acquire higher degradative power to support oncogenic growth.
Insights
TRIM11 activates the proteasome by blocking USP14, enhancing protein degradation and cell survival. This TRIM11-proteasome pathway is crucial for tumor growth and poor clinical outcomes in cancer.
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- The proteasome is essential for protein homeostasis and cell regulation, with its dysfunction linked to diseases like cancer.
- Mechanisms controlling proteasome activity in both normal and malignant cells are not fully understood.
Purpose of the Study:
- To investigate the role of TRIM11 in regulating proteasome activity and its implications in cancer.
- To elucidate the molecular mechanism by which TRIM11 modulates proteasome function.
Main Methods:
- Co-immunoprecipitation assays to study protein-protein interactions.
- In vitro assays to measure proteasome activity and degradation rates.
- Analysis of TRIM11 expression in tumor samples and correlation with clinical data.
Main Results:
- TRIM11 enhances the degradation of regulatory proteins and increases overall proteolysis.
- TRIM11 binds to the proteasome and USP14, preventing USP14-mediated inhibition and increasing proteasome activity.
- TRIM11 promotes cell survival, is upregulated by heat shock, and is required for tumor growth.
Conclusions:
- TRIM11 is a novel activator of the proteasome, defining a pathway for adjusting proteasome activity.
- TRIM11's ability to enhance proteasome activity supports oncogenic growth and is associated with poor patient survival.
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