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Regulation of ER homeostasis by UFM1, the enigmatic Ubiquitin-like modifier

; University of Dundee

Yogesh studied Chemical Engineering at the Birla Â鶹ÊÓƵ of Tech & Sci (BITS), Pilani, India. He did his PhD at the Max Planck Â鶹ÊÓƵ of Immunobiology, Germany (2008) working on B cell signalling. To learn to apply structural biology to study cell signalling, he did his postdoc at the Medical Research Council Laboratory of Molecular Biology (MRC LMB), Cambridge (2009-12) funded by Marie Curie and EMBO fellowships. He set up his independent lab at the MRC Protein Phosphorylation & Ubiquitylation Unit in 2013. The research goals of his lab are to understand the fundamental principles of how posttranslational modification (PTM) of proteins with ubiquitin and ubiquitin-like modifiers (UBL) alter protein function and signal transduction to maintain cellular homeostasis. Yogesh is the recipient of an European Research Council (ERC) Starting Grant (2016), EMBO Young Investigator (2016), Lister Research Prize (2017) & ERC Consolidator Grant (2021). He is presently Professor of Cellular Biochemistry at University of Dundee.

Protein UFMylation, the covalent attachment of the ubiquitin-like modifier UFM1 to substrates, is emerging as a posttranslational modification essential for endoplasmic reticulum and cellular homeostasis. Mutations that disrupt UFMylation are found in several human neurodevelopmental disorders, highlighting the importance of this modification. A single lysine residue on endoplasmic reticulum (ER) membrane bound ribosomes gets modified with UFM1. However, we have a poor understanding of how UFM1 is attached to ribosomes and the functional consequence of this modification. I will present our latest findings where we use a rebuilding approach to define the molecular players and principles of protein UFMylation. I will present our work which reveals regulatory principles driving the attachment and removal of UFM1 from endoplasmic reticulum (ER) membrane-bound ribosomes to regulate protein homeostasis at the ER. I will also discuss important roles we have uncovered for UFMylation in T lymphocytes and immune responses.