The Role of ZNF598 in Translational Quality Control: Mechanisms and Emerging Biological Functions

Figure 1. Domain architecture of ZNF598 and the canonical ribosome-associated quality control (RQC) pathway. (A) Schematic representation of the domain architecture of human ZNF598 (NM_178167.4). ZNF598 contains a RING finger domain and a C2H2 zinc-finger domain. (B) The canonical RQC pathway. Upon ribosome collision and translational stalling, ZNF598 recognizes collided ribosomes and ubiquitinates the 40S ribosomal proteins RPS10. The ubiquitinated 40S subunit subsequently recruits the ASC-1 complex (ASCC), which promotes the dissociation of the stalled 80S ribosome. Following ribosome splitting, the mRNA and 40S subunit are recycled, whereas the 60S large subunit remains associated with the peptidyl-tRNA-containing nascent polypeptide. The adaptor protein NEMF then binds to the stalled 60S subunit and serves as a platform for the recruitment of LTN1, forming the NEMF–LTN1 complex. In addition, NEMF mediates C-terminal alanine/threonine tailing (CAT-tailing) of the nascent chain, thereby exposing internal lysine residues and facilitating their accessibility for ubiquitination. As an E3 ubiquitin ligase, LTN1 catalyzes the conjugation of ubiquitin chains to the exposed lysine residues,…

Figure 2. Dual roles of ZNF598 in translational repression and ribosome-associated quality control. (A) Translation of internal poly(A) sequences or the poly(A) tail of nonstop mRNAs activates ZNF598, which catalyzes the monoubiquitination of RPS10 at Lys138 and Lys139 on the 40S ribosomal subunit. This ubiquitination event promotes ribosome stalling and triggers the ribosome-associated quality control (RQC) pathway. In the absence of ZNF598, RPS10 is not monoubiquitinated, resulting in defective ribosome stalling and continued translation through poly(A) sequences (poly(A) readthrough). (B) Besides mediating the RQC pathway, ZNF598 functions as a scaffold protein that recruits GIGYF2 and 4EHP to defective mRNAs through direct protein–protein interactions. Cap binding by 4EHP inhibits translation initiation complex assembly, thereby preventing additional ribosomes from initiating translation on the aberrant mRNA.