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

The ribosome collision due to translational stalling is recognized as a problematic event in translation by E3 ubiquitin ligase Hel2, leading to the non-canonical subunit dissociation followed by targeting of the faulty nascent peptides for degradation. Although Hel2-mediated quality control greatly contributes to maintaining cellular protein homeostasis, its physiological role in dealing with endogenous substrates remains unclear. Here we present a genome-wide analysis, based on selective ribosome profiling, to survey the endogenous substrates for Hel2. This reveals that Hel2 preferentially binds to the pre-engaged secretory ribosome-nascent-chain complexes (RNCs), which is translating upstream of targeting signals. Notably, Hel2 recruitment into secretory RNCs is elevated in the SRP-deficient condition; furthermore, the mitochondrial defects caused by insufficient SRP are enhanced by hel2 deletion, together with the mistargeting of secretory proteins into mitochondria. Collectively, our findings provide novel insights into the risk management in the secretory pathway for maintaining the cellular protein homeostasis. 2 replicates in 12 different treatment