Diagram of a human cell showing examples of how QC can be localized to one organelle in the cell, excluded from particular areas, or locally regulated by the cytoskeleton. Each of the three sections corresponds to a particular subject heading within the manuscript. (A) Local QC. Stalled ribosomes associated with the ER and mitochondria are regulated by dedicated QC pathways. Here, we show the examples of (1) UFMylation of stalled ribosomes and NMD via recruitment of UPF1 by NBAS on the ER, and (2) modulation of the RQC response on the mitochondrial surface by ANKZF1 and NOT4-mediated modification of ABCE1. (B) QC excluded. RNA granules protect mRNAs by shielding them from QC proteins. Here, we include the example of Not1-containing-assemblysomes where proteasome assembly takes place. The granules allow interactions between nascent chains on paused ribosomes to occur without detection by QC factors. (C) QC regulated. A protrusion at the bottom of the cell shows enrichment of ribosomes that support increased translation of mRNAs that are transported to these regions. This phenomenon occurs in different cell types with complex morphology, such as neurons and intestinal cells. Dynamics of actin polymerization are shown as an example of how eIF2α phosphorylation (and ISR activation) could be regulated. Phosphorylation occurs as a result of GCN1-sensed ribosome collisions and more frequent collisions may be expected in this region due to high ribosome loading. Competition between GCN2 and IMPACT for GCN1 would limit this phosphorylation. (D) Examples of QC with localized roles in a neuron. Shown are the examples of QC factors being excluded from sensing stalled ribosomes during transport in axons and potential repair (a type of QC) of damaged ribosomes in the end branches of the axon. Created with BioRender.com.
