How cells defend their cytosol against invading bacteria
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The cytosol of mammalian cells appears an attractive niche for bacterial pathogens since it is rich in nutrients. However, perhaps surprisingly, most intracellular bacteria avoid the cytosol and rather reside inside vesicles. We think this paradox is caused by autophagy and other powerful, but poorly characterized, cell-autonomous immune mechanisms that protect the cytosol (reviewed in Randow et al., Science 2013).
Guided by the importance of cell-autonomous immunity as the sole defender of unicellular organisms, our lab has identified several novel genes that protect the cytosol of human cells against bacterial invasion, for example Galectin-8, a receptor that senses membrane damage caused by bacteria entering the host cytosol (Thurston et al., Nature 2012), LUBAC, an E3 ubiquitin ligase that attaches M1-linked ubiquitin chains directly onto cytosol-invading bacteria (Noad, Nature Microbiol 2017), and GBPs, a family of IFN-induced proteins that attack the bacterial surface to immobilize the pathogen in the host cytosol (Wandel, Cell Host Microb 2017). Our most recent work on LUBAC and GBPs revealed a novel principle of cell-autonomous immunity, namely that cells transform bacteria into pro-inflammatory and anti-bacterial signalling platforms by coating their surface with polyvalent protein aggregates.
A position for an enthusiastic PhD student interested in cell-autonomous defence against bacteria or viruses is available. Work will focus on the transformation of bacterial surfaces into signalling platforms. Potential projects include the identification of novel E3 ligases that ubiquitylate bacteria, the investigation how GBPs detect bacteria, and the identification of novel anti-bacterial effector mechanisms triggered by polyvalent protein coats on bacterial surfaces.
Randow, F., MacMicking, J.D., and James, L.C. (2013).
Cellular self-defense: how cell-autonomous immunity protects against pathogens.
Science 340, 701–706.
Thurston, T.L.M., Wandel, M.P., Muhlinen, von, N., Foeglein, A., and Randow, F. (2012).
Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion.
Nature 482, 414–418.
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.
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.