LPS ubiquitylation and cell-autonomous immunityGroup Leader Page
Our ability to fight infections relies on the capacity of our immune system to defend our body and on the skills of individual cells to defend themselves. The contributions of professional immune cells to innate and acquired immunity have received much attention. Much less is known about the principles of cell-autonomous immunity. Inspired by the ability of unicellular organisms to rely exclusively on cell-autonomous defences, we investigate how mammalian cells protect their interior against bacterial invasion (reviewed in Randow, Science 2013).
Our recent work has revealed a novel principle of cell-autonomous immunity. We discovered that mammalian cells convert cytosol-invading bacteria into pro-inflammatory and anti-bacterial signalling platforms through the deposition of host proteins into polyvalent arrays at bacterial surfaces. Examples include the ubiquitylation of bacterial LPS (the first known instance of ubiquitylation targeting a non-proteinaceous substrate) and the deposition of GBPs, a family of interferon-induced GTPases, which are essential for anti-bacterial autophagy and caspase-4—dependent pyroptotic cell death, respectively (Otten Nature 2021, Wandel, Nat Immunol 2020, Falcon Mol Cell 2019, Noad Nat Microbiol 2017, Wandel, Cell Host Microbe 2017).
A position for an enthusiastic PhD student interested in cell-autonomous defence against cytosolic pathogens is available. The project will focus on the transformation of bacterial surfaces into signalling platforms. Potential projects include the functional and structural characterization of LPS ubiquitylation by RNF213, the investigation how GBPs detect bacteria, and the identification of novel anti-bacterial effector mechanisms triggered by polyvalent protein coats on bacterial surfaces.
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.
Wandel, M.P., Kim, B.-H., Park, E.-S., Boyle, K.B., Nayak, K., Lagrange, B., Herod, A., Henry, T., Zilbauer, M., Rohde, J., MacMicking, J., Randow, F. (2020)
Guanylate-binding proteins convert cytosolic bacteria into caspase-4 signaling platforms.
Nat Immunol 21, 880–891.
Ravenhill BJ, Boyle KB, von Muhlinen N, Ellison CJ, Masson GR, Otten EG, Foeglein A, Williams R, Randow F. (2019)
The cargo receptor NDP52 initiates selective autophagy by recruiting the ULK complex to cytosol-invading bacteria.
Mol Cell 74, 320-329.
Wandel, M., Pathe, C., Werner, E., Ellison, C., Boyle, K., Rohde, J., Randow, F. (2017).
GBPs inhibit motility of Shigella flexneri but are targeted for degradation by the bacterial ubiquitin ligase IpaH9.8.
Cell Host and Microbe 22, 5-7-518.
Noad, J., Malsburg, von der, A., Pathe, C., Michel, M.A., Komander, D., and Randow, F. (2017).
LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-κB.
Nat. Microbiol 2, 17063.
Randow, F., MacMicking, J.D., and James, L.C. (2013).
Cellular self-defense: how cell-autonomous immunity protects against pathogens.
Science 340, 701–706.