Function of the GID Ubiquitin-Ligase Complex in the Control of Metabolism and Organismal Lifespan

• Applicant: Professor Dr. Thorsten Pfirrmann
• Subject Area: Biogerontology and Geriatric Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566709590

Ageing is a complex biological process regulated by signaling pathways that integrate environmental and physiological cues, such as nutrient availability, to maintain cellular energy homeostasis and influence lifespan. The ubiquitin-proteasome system (UPS) plays a crucial role in controlling energy metabolism by regulating protein turnover, localization, and activity of metabolic factors. However, the specific components of the UPS involved in cellular energy regulation and ageing remain poorly understood. The GID (glucose-induced degradation deficient) complex is an evolutionarily conserved E3 ubiquitin ligase complex that regulates energy homeostasis and ageing in various species. In yeast, the GID complex targets key gluconeogenic enzymes for degradation during glucose-rich conditions, thereby controlling catabolite degradation. Recent evidence suggests that the mammalian GID complex regulates energy metabolism through AMP-activated protein kinase (AMPK), a master regulator of energy homeostasis. Our preliminary data reveal that the vertebrate GID complex ubiquitinates phosphorylated AMPK, preventing its overactivation. Loss of GID activity results in constitutive AMPK activation, inducing catabolic pathways such as autophagy and fatty acid oxidation, independent of cellular energy status. Strikingly, in Caenorhabditis elegans, RNAi-mediated knockdown of conserved GID complex subunits significantly extends lifespan, highlighting its role in longevity regulation. In this project, we aim to unravel the mechanistic interplay between the GID complex and AMPK in ageing. We will generate C. elegans mutants, including RING-dead and knockout lines for gid-2, to investigate the impact of complete GID loss on lifespan. We will dissect the specific roles of AMPK paralogs, aak-1 and aak-2, in mediating GID-dependent longevity, using genetic and molecular approaches. Additionally, we will explore how the GID complex intersects with other metabolic and ageing regulators, such as dietary restriction and insulin/IGF signaling. To assess healthspan, we will measure age-dependent physiological functions, including locomotion and sensory responses, in GID-deficient worms. Our research will also focus on identifying AMPK as a potential substrate of the GID complex in C. elegans, investigating protein-protein interactions, co-localization, and ubiquitination using advanced genetic and biochemical methods. Preliminary findings suggest that aak-1 may act as a substrate for GID-mediated ubiquitination, with implications for its novel role in lifespan regulation. This project will provide a comprehensive understanding of the GID complex in modulating energy homeostasis and ageing, uncovering potentially conserved mechanisms relevant for the development of therapeutic strategies for age-related diseases and lifespan extension.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Karl Emanuel Busch