Asc1, Hel2, and Slh1 couple translation arrest to nascent chain degradation

Premature arrest of protein synthesis within the open reading frame elicits a protective response that degrades the incomplete nascent chain. In this response, arrested 80S ribosomes are split into their large and small subunits, allowing assembly of the ribosome quality control complex (RQC), which targets nascent chains for degradation. How the cell recognizes arrested nascent chains among the vast pool of actively translating polypeptides is poorly understood. We systematically examined translation arrest and modification of nascent chains in Saccharomyces cerevisiae to characterize the steps that couple arrest to RQC targeting. We focused our analysis on two poorly understood 80S ribosome-binding proteins previously implicated in the response to failed translation, Ascl and HeI2, as well as a new component of the pathway, Slhl, that we identified here. We found that premature arrest at ribosome stalling sequences still occurred robustly in the absence of Ascl, HeI2, and Slhl. However, these three factors were required for the RQC to modify the nascent chain. We propose that Ascl, HeI2, and Slhl target arresting ribosomes and that this targeting event is a precondition for the RQC to engage the incomplete nascent chain and facilitate its degradation.