Specificity and functions of GID ubiquitin ligases in proteostasis and metabolism

• Applicant: Anton Khmelinskii, Ph.D.
• Subject Area: Cell Biology ; Biochemistry
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 557542771

Selective protein degradation is involved in most cellular processes and contributes to proteostasis through the removal of unnecessary or abnormal proteins. The ubiquitin-proteasome system plays a key role in selective protein degradation, whereby ubiquitin ligases mark proteins with ubiquitin for degradation by the 26S proteasome. Numerous ubiquitin ligases are modular multi-subunit assemblies that recruit substrates using interchangeable substrate receptors, which can recognize substrates with different degradation signals and thus expand the substrate repertoire of a ubiquitin ligase. The GID (glucose-induced degradation deficient) complex has recently emerged as a paradigmatic example of ubiquitin ligases employing interchangeable substrate receptors. The GID complex is conserved from yeast to humans, where it is known as the CTLH (C-terminal to LisH) complex. Both GID and CTLH subunits can assemble into multiple distinct large complexes that appear to recognize and ubiquitinate different substrates. Thus, unsurprisingly, GID/CTLH ubiquitin ligases have been implicated in a variety of processes, including metabolic regulation, cell proliferation, embryonic development and cell differentiation. Furthermore, mutations in CTLH subunits have been linked to numerous pathologies, including cancer and neurodevelopmental disorders, highlighting the importance of understanding this ubiquitin ligase. However, how GID complexes perform this variety of functions and how they recognize different substrates is not well understood. In this proposal, we will use the budding yeast Saccharomyces cerevisiae as a model to systematically identify substrates and functions of different GID complexes, and to characterize substrate receptors of this ubiquitin ligase.

• DFG Programme: Research Grants