Thursday, April 25, 2024
4/25/2024
Project Summary Ribosomes are macromolecular machines that decode the genome. Quality control mechanisms that ensure the fidelity of this process are thus of paramount importance cellular and organismal viability. Ribosomes move at variable rates, slowing down or even pausing to facilitate organelle targeting, domain folding and co-translational assembly, but prolonged stalls are deleterious to cells because they can deplete functional ribosomes and produce highly toxic truncated nascent chains. Stalls that occur on endoplasmic reticulum (ER) ribosomes are even more damaging because they additionally obstruct the translocons through which all secreted and membrane proteins must transit en route to the secretory pathway. Ribosome quality control (RQC) is a conserved and essential process that rescues stalled 60S subunits by extracting the obstructing nascent chain and degrading it by the UPS. Despite immense progress in the past decade in defining RQC for cytosolic ribosome, the how RQC operates for ER-stalled ribosomes is almost completely uninvestigated. Recently my lab discovered that UFMylation – the process by which UFM1, a small ubiquitin-like protein is conjugated to ribosomes — plays a central and essential role specifically in adapting RQC to proteins synthesized at the ER. The three specific aims described in this proposal seek to build on the foundation provided by our extensive preliminary data to define the mechanism by which nascent chains that obstruct ribosomes that stall on ER translocons are extracted and degraded. In aim 1 we will conduct a systematic dissection of the RQC machinery to define the role of known RQC required to resolve stalled ribosomes at the ER. In aim 2 we will define the interplay between ribosome UFMylation and RQC and dentify the readers of UFMylated ribosomes at the ER. In aim 3 we will determine the structure of UFMyulated ribosomes and the E3 ligase that conjugates UFM1 to the ribosome.
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