UFMylation regulates translational homeostasis and cell cycle progression

Abstract

UFMylation, the posttranslational modification of proteins with ubiquitin fold modifier 1 (UFM1) is essential for metazoan life and is associated with multiple human diseases. Although UFMylation has been linked to endoplasmic reticulum (ER) stress, its biological functions and relevant cellular targets beyond the ER are obscure. Here, we show that UFMylation directly controls translation and cell division in a manner otherwise known for cellular homeostasis-sensing pathways such as mTOR. By combining cell cycle analyses, mass spectrometry and ribosome profiling we demonstrate that UFMylation is required for eIF4F translation initiation complex assembly and recruitment of the ribosome. Interference with UFMylation shuts down global translation, which is sensed by cyclin D1 and halts the cell cycle independently of integrated stress response signalling. Our findings establish UFMylation as a key regulator of translation and uncover a pathway that couples translational homeostasis to cell cycle progression via a ubiquitin-like modification.