UFMylation is essential for ribosome-associated quality control at the endoplasmic reticulum

What is it about?

During translation, ribosomes can encounter problems that cause them to stall. These incidents generate large ribosomal subunits that are incapacitated by truncated nascent proteins that must be destroyed to maintain protein synthetic capacity and avert proteotoxicity. The ribosome-associated quality control (RQC) pathway extracts these truncated nascent proteins from stalled ribosomal subunits and targets them for degradation via the proteasome. Ribosomes that stall during the synthesis of secretory proteins into the endoplasmic reticulum (ER) are fundamentally different from those that stall in the cytosol, as they produce truncated nascent proteins that are shielded from cytosolic proteasomes by the ER membrane and the tightly sealed junction between the ribosome and the nascent protein translocation pore (translocon). Our findings indicate that conjugation of the ubiquitin-like protein UFM1 (i.e., UFMylation) to these stalled ribosomes at the ER facilitates RQC for secretory proteins by weakening the junction between the ribosome and the translocon, thus enabling proteasomes to access the truncated proteins.

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Photo by National Cancer Institute on Unsplash

Photo by National Cancer Institute on Unsplash

Why is it important?

Although UFMylation was known to be critical for ER homeostasis, its exact biological function has remained elusive for nearly 20 years. Our findings provide new insight into the role of this post-translational modification in promoting rescue of ribosomes that stall during co-translational translocation of secretory proteins into the endoplasmic reticulum, thus performing the critical role of maintaining translational fidelity for the one third of the human proteome that is synthesized at the ER.