蛋白稳态和氧化还原平衡是维持机体正常功能的两个相互关联的分子事件 。在癌症中，破坏蛋白稳态和氧化还原平衡一方面是杀死癌细胞的有效途径，另一方面又可能促进肿瘤发生和耐药。具体后果可能与组织特异性及应激压力的强度和时长有关。我们前期结果表明TRIM21通过泛素化自噬受体分子p62负向调节p62-Nrf2抗氧化通路，临床数据显示TRIM21高表达与肝细胞肝癌（HCC）发生呈正相关。据此我们假设TRIM21通过调节p62来抑制自噬和抗氧化反应并促进HCC的发生发展。我们将进行以下实验：1）TRIM21介导的p62泛素化与p62其它翻译后修饰间的分子关系；2）TRIM21是否调节体内自噬；3）TRIM21在HCC发生发展中的作用。该研究将阐明TRIM21调节p62的详细分子机制及其在自噬和HCC中的作用。完成该项目将揭示细胞蛋白质稳态和氧化还原平衡新的生物学调节机制，有望为HCC药物研发提供新靶点。

Protein homeostasis (proteostasis) and reduction-oxidation (redox) balance are two tightly regulated and mutually linked molecular events that play critical roles in maintaining normal organismal functions. Disruption of proteostasis and redox balance on one hand may be an effective approach to selectively kill cancer cells, on the other hand may promote oncogenesis and therapy-resistance. The outcome may be determined by tissue specificity and the strength and duration of the stress signaling. We recently reported that an ubiquitin E3 ligase TRIM21 directly interacts with and ubiquitylates the p62, which critically regulates both autophagy as an autophagy receptor and redox balance via the p62-Keap1-Nrf2 antioxidant pathway. Clinical data indicates that elevated TRIM21 expression correlates with increased hepatocellular carcinoma (HCC) incidence. Hence, we propose that TRIM21 inhibits antioxidant reaction and autophagy through p62 ubiquitylation, thereby promotes HCC development. To test this hypothesis, we will study: 1) the molecular relationship between TRIM21-mediated p62 ubiquitylation and other p62 post-translational modifications; 2) how TRIM21 regulates autophagy in vivo; and 3) the role of TRIM21 in HCC development. This study will demonstrate TRIM21 as a novel regulator of p62 in regulating redox balance and autophagy, and will uncover its role in the development of HCC. Accomplishing this project will not only illustrate the new function of TRIM21 in proteostasis and redox balance, but also provide new therapeutic target for HCC treatment.