ZNF598 Is a Quality Control Sensor of Collided Ribosomes

Aberrantly slow translation elicits quality control pathways initiated by the ubiquitin ligase ZNF598. How ZNF598 discriminates physiologic from pathologic translation complexes and ubiquitinates stalled ribosomes selectively is unclear. Here, we find that the minimal unit engaged by ZNF598 is the collided di-ribosome, a molecular species that arises when a trailing ribosome encounters a slower leading ribosome. The collided di-ribosome structure reveals an extensive 40S-40S interface in which the ubiquitination targets of ZNF598 reside. The paucity of 60S interactions allows for different ribosome rotation states, explaining why ZNF598 recognition is indifferent to how the leading ribosome has stalled. The use of ribosome collisions as a proxy for stalling allows the degree of tolerable slowdown to be tuned by the initiation rate on that mRNA; hence, the threshold for triggering quality control is substrate specific. These findings illustrate how higher-order ribosome architecture can be exploited by cellular factors to monitor translation status. Cells contain millions of ribosomes that need to translate mRNAs accurately to maintain homeostasis. Ribosomes that slow excessively during translation must be promptly resolved to avoid disease. Juszkiewicz et al. show that ribosome collisions, a sign of aberrant translation, are detected by the ubiquitin ligase ZNF598 to initiate quality control.