Loewe, Thomas, Pokryzwa, Wojciech, Hoppe, Thorsten, Lorenz, Robin, Balaji, Vishnu, Mueller, Leonie
[
International Worm Meeting,
2021]
Proteostasis is achieved by quality control pathways that support the generation of correctly folded proteins, prevent protein misfolding and remove toxic proteins. The quality control E3 ligase CHIP ubiquitylates damaged proteins consigned by chaperone partners for disposal through the endo-lysosomal pathway, proteasomal degradation, or autophagy. Additionally, CHIP has been reported to modulate essential signaling pathways by specifically delivering a myriad of native proteins to destined fates homeostasis (Paul I and Ghosh M.K., 2015). We aimed at understanding the substrate specificity and processivity through a "structure to function" approach, by examining the modeled 3D structure of the C. elegans ortholog of CHIP, CHN-1, based on the reported structure of murine CHIP (Zhang M et al., 2005). Using C. elegans and mammalian cells as model system and with various genetic and biochemical analyses, we demonstrate that monomeric CHN-1/CHIP has preserved ubiquitylation activity and promotes longevity via the DAF-2 Insulin-like signaling pathway (Tawo R et al., 2017). Our data reveal that the CHN-1/CHIP autoubiquitylation and its chaperone binding interplay modulates the alteration between monomer and dimer (Balaji V and Hoppe T., 2020). Together, the conserved dimer-monomer transition provides a molecular switch regulating CHN-1/CHIP activity in response to proteotoxic stress and aging.