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

Cole S Sitron,Joseph H Park,Onn Brandman

doi:10.1261/rna.060897.117

Abstract

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, Asc1 and Hel2, as well as a new component of the pathway, Slh1, that we identified here. We found that premature arrest at ribosome stalling sequences still occurred robustly in the absence of Asc1, Hel2, and Slh1. However, these three factors were required for the RQC to modify the nascent chain. We propose that Asc1, Hel2, and Slh1 target arresting ribosomes and that this targeting event is a precondition for the RQC to engage the incomplete nascent chain and facilitate its degradation.

Highlights

Cells are equipped with multiple mechanisms to identify and respond to defective protein
We propose that Asc1, Hel2, and Slh1 target arresting ribosomes and that this targeting event is a precondition for the ribosome quality control complex (RQC) to engage the incomplete nascent chain and facilitate its degradation
Epistasis experiments suggested that Asc1, Hel2, and Slh1 act upstream of the RQC (Fig. 1C)

Summary

Introduction

Cells are equipped with multiple mechanisms to identify and respond to defective protein Aberrant species such as misfolded proteins can be identified via direct interactions with quality-control components such as chaperones and ubiquitin ligases (Hartl and Hayer-Hartl 2009; Shao and Hegde 2016). These sensors recognize unique features of defective proteins (e.g., exposure of hydrophobic patches) and repair or mark them for degradation (Hartl and Hayer-Hartl 2009; Shao and Hegde 2016). Cells are able to degrade a class of defective protein with no apparent defects: nascent chains arising from stalled mRNA translation that does not terminate normally (Brandman and Hegde 2016). Degradation of the products of stalled translation is conserved throughout Eukarya (Passos et al 2009; Shao et al 2013, 2015; Shao and Hegde 2014; Ikeuchi et al 2016), and failures in this response have been linked to dysregulation of protein homeostasis (Choe et al 2016; Defenouillere et al 2016; Yang et al 2016; Yonashiro et al 2016) and neurodegenerative phenotypes (Chu et al 2009; Ishimura et al 2014)

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Conclusion