Regulation of protein translation by TRIM21

AbstractRegulation of translation initiation is essential for maintenance of protein homeostasis and typically involves the phosphorylation of translation initiation factor eIF2 in eukaryotes. In response to stressors, cells employ eIF2-dependent signaling to control translation initiation, which regulates multiple biological and physiological processes. However, the precise regulatory mechanism remains unclear. In this study, we focus on the role of TRIM21 in the regulation of protein translation mediated by protein kinase R (PKR), one of the classic kinases that phosphorylates eIF2. TRIM21 deficiency enhances the activation of PKR under different types of stress. TRIM21 interacts with PKR, and the E3 ligase activity of TRIM21 is crucial for stress-triggered PKR inactivation. TRIM21 interacts with the PKR phosphatase PP1 and promotes K6-linked polyubiquitination of PP1 under stresses. Ubiquitination of PP1 augments its interaction with PKR, causing PKR inactivation and subsequent dephosphorylation of eIF2, initiating protein synthesis. Moreover, TRIM21 constitutively restricts viral infection by reversing PKR-mediated inhibition of the protein synthesis of intrinsic antiviral genes. The TRIM21-PP1 axis acts as a newly discovered program that regulates PKR-associated protein synthesis and broadens our knowledge of antiviral genes. Moreover, TRIM21-mediated regulation of PKR activation provides evidence that TRIM21 may anticipate the interferon-dependent immunotherapy. Our study highlights the essential role of TRIM21 in regulating protein translation and may provide a novel target for the treatment of translation-associated diseases.