Failure to release from the ER translocon induces 60S ribosome degradation

Ribosome malfunction can have detrimental effects on cells, but the specific mechanisms behind ribosome degradation in mammalian cells are not well understood. Researchers have now developed a CRISPR screening approach to identify key regulators of ribosome turnover. Their findings reveal that the loss of protein UFMylation is linked to the degradation of the 60S ribosomal subunit.

UFMylation normally releases the 60S subunit from the endoplasmic reticulum (ER) translocon, allowing for its degradation. Without UFMylation, single-molecule tracking and optogenetic proximity labeling techniques show that ER-associated 60S subunits accumulate and are selectively degraded. This process, known as translocon-associated large subunit degradation (TLSD), is independent of the lysosome and specifically occurs in nondividing, contact-inhibited cells.

The degradation process relies on a protein called R3HDM4, which the researchers have named TLSD1. When UFMylation is absent, TLSD1 relocates to the ER and facilitates the degradation of 60S subunits. These results suggest that the release of the 60S subunit from the ER translocon acts as a checkpoint for ribosome function, shedding light on the genetic links between TLSD1 and neuronal health and erythropoiesis.