Journal Article

TRIM11 activates the proteasome and promotes overall protein degradation by regulating USP14

Yang, Xiaolu, Johns, Eleanor M., Chen, Liang, Zhu, Guixin

2018

Overview

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. The proteasome-bound ubiquitinase USP14 plays an important role in determining proteasome activity and substrate specificity. Here the authors show that TRIM11, a member of the mammalian tripartite motif family, regulates USP14 and is an important activator of the proteasome.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/106 / 13/109 / 13/2 / 13/31 / 13/51 / 13/95 / 631/337/474/1768 / 631/80/474/2085 / 82/80 / 82/83 / Animals / Biodegradation / Cancer / Carcinogenesis / Cell Line / Cell Line, Tumor / Cell Proliferation - physiology / Cell survival / Cell Survival - physiology / Cells, Cultured / Degradation / Deubiquitinating Enzymes - metabolism / Enzyme Activation / Heat shock / Homeostasis / Humanities and Social Sciences / Humans / Mice / multidisciplinary / Protease inhibitors / Proteasome Endopeptidase Complex - metabolism / Proteasomes / Protein Binding / Protein Conformation / Protein Folding / Proteins / Proteolysis / Quality control / Regulatory proteins / Science / Science (multidisciplinary) / Substrate inhibition / Survival / Tripartite Motif Proteins - chemistry / Tripartite Motif Proteins - metabolism / Tripartite Motif Proteins - physiology / Tumor cells / Ubiquitin Thiolesterase - antagonists & inhibitors / Ubiquitin Thiolesterase - chemistry / Ubiquitin Thiolesterase - metabolism / Ubiquitin-Protein Ligases - chemistry / Ubiquitin-Protein Ligases - metabolism / Ubiquitin-Protein Ligases - physiology / Up-Regulation