About the Project
Ubiquitylation is essential for eukaryotic life. Until recently, proteins were the only substrates known to be modified with ubiquitin. Then we reported that the E3 ligase RNF213 ubiquitylates lipopolysaccharide (LPS) on bacteria that invade the host cytosol. LPS ubiquitylation marks bacteria for selective autophagy, thereby protecting the host from infection. Other non-protein substrates of ubiquitylation have since been identified, but the consequences of this modification remain largely unknown. We recently discovered that mice lacking RNF213 accumulate insoluble glycogen (polyglucosan bodies) in specific brain regions, a pathology reminiscent of human Lafora disease. RNF213 selectively ubiquitylates poorly branched glycogen, triggering its removal by selective autophagy and thereby preventing polyglucosan accumulation. Non-protein ubiquitylation is a nascent field with clear importance in immune defense against pathogens, biomolecular quality control and likely many other cellular activities. Students interested in investigating the molecular mechanism and physiological consequences of non-protein ubiquitylation are invited to apply.
Funding Notes
References
Otten, E.G., Werner, E., Crespillo-Casado, A., Boyle, K.B., Dharamdasani, V., Pathe, C., Santhanam, B., and Randow, F. (2021). Ubiquitylation of lipopolysaccharide by RNF213 during bacterial infection. Nature 594, 111–116.
Crespillo-Casado, A., Pothukuchi, P., Naydenova, K., Yip, M.C.J., Young, J.M., Boulanger, J., Dharamdasani, V., Harper, C., Hammoudi, P.-M., Otten, E.G., Randow, F. (2024). Recognition of phylogenetically diverse pathogens through enzymatically amplified recruitment of RNF213. EMBO Rep. 25, 4979–5005.
Naydenova, K., Boyle, K.B., Pathe, C., Pothukuchi, P., Crespillo-Casado, A., Scharte, F., Hammoudi, P.-M., Otten, E.G., Alto, N.M., and Randow, F. (2025). Shigella flexneri evades LPS ubiquitylation through IpaH1.4-mediated degradation of RNF213. Nat. Struct. Mol. Biol., 1–11.
Yip, M.C.J., Naydenova, K., Otten, E.G., Heatley, A., Moe, A., Anton, L., de los Reyes-Ramírez, L., Jolin, H.E., Langevin, F., Wiacek, M., Franco, C., Bertolotti, A., Kukulski, W., McKenzie, A.N.J., Randow, F. (2026). Quality control of glycogen through direct ubiquitylation by RNF213. Nature (in press).
