Pathological mechanisms of the ubiquitin E3 ligases TRIM27, TRIM32 and TRIM45 in cancer and autophagy

Abstract

TRIM proteins are E3 ubiquitin ligases, meaning that they modify other substrate proteins with ubiquitin, either tagging them for destruction or influencing their function. We have focused on three TRIM proteins, TRIM32, TRIM45, and TRIM27. Using in silico and in vitro methods we have further elucidated the importance of TRIM proteins in tumorigenesis and autophagy. In our study we found TRIM32 to be associated with head and neck cancer and patients with high expression of TRIM32 having worse prognosis. TRIM32 might worsen the prognosis by increasing glycolysis through MYC signaling, that could increase the expression of glycolytic proteins, including HK2 and LDHA. This may further promote tumor growth, metastasis, and proliferation. We also identified TRIM45 as an estrogen receptor (ER) associated gene, and that higher TRIM45 expression improved the prognosis of ER-positive breast cancer patients. The glycoprotein STC2 was found to be upregulated in response to elevated TRIM45 expression and contributed to better prognosis. TRIM45 might be an estrogen responsive gene, but the exact mechanism behind TRIM45 regulation and its cooperation with STC2 to improve prognosis needs further research. Lastly, in our project, TRIM27 was observed to induce clustering of mitochondria by interacting with the selective autophagy receptor SQSTM1/p62. Additionally, the kinase TBK1 was involved in the clustering process. TRIM27 is suspected to act as a scaffold for the activation of TBK1 and SQSTM1/p62 to promote clustering of mitochondria and mitophagy.