TRIM21 enhances bortezomib sensitivity in multiple myeloma by halting prosurvival autophagy

Bortezomib (bort) is an effective therapeutic agent for patients with multiple myeloma (MM); however, most patients develop drug resistance. Autophagy, a highly conserved process that recycles cytosol or entire organelles via lysosomal activity, is essential for the survival, homeostasis, and drug resistance in MM. Growing evidence has highlighted that E3 ligase tripartite motif-containing protein 21 (TRIM21) not only interacts with multiple autophagy regulators but also participates in drug resistance in various cancers. However, to date, the direct substrates and additional roles of TRIM21 in MM remain unexplored. In this study, we demonstrated that low TRIM21 expression is a factor for relapse in MM. TRIM21 knockdown (KD) made MM cells more resistant to bort, whereas TRIM21 overexpression (OE) resulted in increased MM sensitivity to bort. Proteomic and phosphoproteomic studies of TRIM21 KD MM cells showed that bort resistance was associated with increased oxidative stress and elevated prosurvival autophagy. Our results showed that TRIM21 KD MM cell lines induced prosurvival autophagy after bort treatment, suppressing autophagy by 3-methyladenine treatment or by the short hairpin RNA of autophagy-related gene 5 (ATG5)-restored-bort sensitivity. Indeed, ATG5 expression was increased and decreased by TRIM21 KD and OE, respectively. TRIM21 affected autophagy by ubiquitinating ATG5 through K48 for proteasomal degradation. Importantly, we confirmed that TRIM21 could potentiate the antimyeloma effect of bort through in vitro and in vivo experiments. Overall, our findings define the key role of TRIM21 in MM bort resistance and provide a foundation for a novel targeted therapeutic approach.