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

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.

TRIM11 cooperates with HSF1 to suppress the anti-tumor effect of proteotoxic stress drugs

“…Conversely, overexpression of TRIM11 dramatically increased the HSF1 protein level in the nuclear ( Figure 5(d)), indicating that TRIM11 facilitates the nuclear translocation of HSF1. Moreover, we observed that both TRIM11 and HSF1 were increased in the nuclear fraction during proteotoxic stress (heat shock at 43°C) ( Figure 5(e)), consistent with our previous finding that TRIM11 is up-regulated upon heat shock stress [15].…”

“…We previously reported that majority of TRIM family genes is up-regulated during cell transformation and several of them also contribute to PQC, while TRIM11 is the most potent one in removing aggregated proteins through the proteasome and autophagy [14,15]. Here, we reveal that TRIM11 antagonizes the proteotoxic stress in tumor cells by cooperating with HSF1.…”

“…It has been reported that several TRIM family proteins, such as TRIM24, TRIM32 and TRIM37, can function as oncogenes and are potential targets for cancer therapy [29][30][31]. TRIM11 also has a crucial role for tumor growth [14,15,32]. Besides, we determined that TRIM11 effectively protects tumor cells against various drugs induced proteotoxic stresses.…”

“…We recently showed that TRIM11 controls the removal of misfolded proteins and guards global proteostasis [14,15]. We reasoned that TRIM11 might help tumor cell to survive under various proteotoxic stresses conditions.…”

“…Recently, we found that several of TRIM family members are central regulators of the PQC system, e.g. TRIM19 (also known as PML) degrades the nuclear misfolded proteins via a mechanism involving sequential SUMOylation and ubiquitination [13]; TRIM11 effectively removes both the nuclear and cytoplasmic aberrant proteins, and it also directly activates the proteasome [14,15]. However, whether TRIM11 responds to the proteotoxic stresses and how it is related to chaperone systems remain largely unknown.…”