Mechanochemical forces regulate the composition and fate of stalled nascent chains.

The ribosome-associated quality control (RQC) pathway resolves stalled ribosomes. As part of RQC, stalled nascent polypeptide chains (NCs) are appended with CArboxy-Terminal amino acids (CAT tails) in an mRNA-free, non-canonical elongation process. CAT tail composition includes Ala, Thr, and potentially other residues.

A new way of D/Ealing with protein misfolding.

Huang et al. (2021) show that proteins containing aspartate- and glutamate-rich stretches represent a putative new class of ATP-independent molecular chaperones that operate on diverse client proteins in vitro and protect bona fide interactors against aggregation in cells.

Detection and Degradation of Stalled Nascent Chains via Ribosome-Associated Quality Control.

Stalled protein synthesis produces defective nascent chains that can harm cells. In response, cells degrade these nascent chains via a process called ribosome-associated quality control (RQC). Here, we review the irregularities in the translation process that cause ribosomes to stall as well as how cells use RQC to detect stalled ribosomes, ubiquitylate their tethered nascent chains, and deliver the ubiquitylated nascent chains to the proteasome.

Aggregation of CAT tails blocks their degradation and causes proteotoxicity in S. cerevisiae.

The Ribosome-associated Quality Control (RQC) pathway co-translationally marks incomplete polypeptides from stalled translation with two signals that trigger their proteasome-mediated degradation. The E3 ligase Ltn1 adds ubiquitin and Rqc2 directs the large ribosomal subunit to append carboxy-terminal alanine and threonine residues (CAT tails). When excessive amounts of incomplete polypeptides evade Ltn1, CAT-tailed proteins accumulate and can self-associate into aggregates.

CAT tails drive degradation of stalled polypeptides on and off the ribosome.

Stalled translation produces incomplete, ribosome-tethered polypeptides that the ribosome-associated quality control (RQC) pathway targets for degradation via the E3 ubiquitin ligase Ltn1. During this process, the protein Rqc2 and the large ribosomal subunit elongate stalled polypeptides with carboxy-terminal alanine and threonine residues (CAT tails). Failure to degrade CAT-tailed proteins disrupts global protein homeostasis, as CAT-tailed proteins can aggregate and sequester chaperones.

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.