How cells use ubiquitin and autophagy to defend their cytosol against pathogens
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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 reside inside membrane-surrounded vacuoles. We think this paradox is caused by autophagy and other powerful, but poorly characterized, cell-autonomous immune mechanisms that protect the cytosol and which are overcome only by the most adapted pathogens (reviewed in Randow et al., Science 2013).
Our lab has identified several genes that defend the cytosol against bacterial invasion, for example NDP52, a receptor that targets cytosolic bacteria for autophagy (Thurston et al., Nature Immunol 2009), and Galectin-8, a danger receptor that catches bacteria by sensing the membrane damage bacteria cause when entering the host cytosol (Thurston et al., Nature 2012). We also have identified bacterial effector molecules that counteract cellular defences, for example the bacterial E3 ubiquitin ligase IpaH9.8 that degrades cellular GBP proteins to prevent them from attacking bacteria (Wandel et al., Cell Host Microb 2017).
A position for an enthusiastic PhD student interested in cell-autonomous defence against bacteria or viruses is available. Projects could focus either on novel E3 ligases that ubiquitylate cytosol-invading bacteria, on a novel danger receptor distinct from galectins, or on the control of anti-bacterial autophagy. Projects will focus on the mechanisms of cell-autonomous immunity and will employ a wide variety of molecular and immunological methods.
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., Ryzhakov, G., Bloor, S., Muhlinen, von, N., and Randow, F. (2009).
The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria.
Nat Immunol 10, 1215–1221.
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.
Wandel, Pathe, Werner, Ellison, Boyle, Malsburg, Rohde, Randow (2017).
GBPs inhibit motility of Shigella flexneri but are targeted for degradation by the bacterial ubiquitin ligase IpaH9.8.
Cell Host Microb in press