The ribosome collision sensor Hel2 functions as preventive quality control in the secretory pathway.

Ribosome collision because of translational stalling is recognized as a problematic event in translation by the E3 ubiquitin ligase Hel2, leading to non-canonical subunit dissociation followed by targeting of the faulty nascent peptides for degradation. Although Hel2-mediated quality control greatly contributes to maintenance of cellular protein homeostasis, its physiological role in dealing with endogenous substrates remains unclear. This study utilizes genome-wide analysis, based on selective ribosome profiling, to survey the endogenous substrates for Hel2. This survey reveals that Hel2 binds preferentially to the pre-engaged secretory ribosome-nascent chain complexes (RNCs), which translate upstream of targeting signals. Notably, Hel2 recruitment into secretory RNCs is elevated under signal recognition particle (SRP)-deficient conditions. Moreover, the mitochondrial defects caused by insufficient SRP are enhanced by hel2 deletion, along with mistargeting of secretory proteins into mitochondria. These findings provide insights into risk management in the secretory pathway that maintains cellular protein homeostasis.