Intracellular bacteria such as Salmonella are a major threat to human health. These disease-causing microorganisms enter human cells cloaked in a host-derived membrane, which forms a structure termed a vacuole. To proliferate, Salmonella then need to access the cytoplasm, a feat that they typically manage through vacuole rupture. Writing in Nature, Otten et al.1 reveal the host’s front-line mode of attack against invading Salmonella — a previously unknown mechanism and machinery that marks Salmonella with the host protein ubiquitin. This tagging sets in motion events that lead to the degradation of the microbial invader.
It was already known that this destruction process involves coating Salmonella with ubiquitin2. The presence of ubiquitin-tagged Salmonella in the cytoplasm launches a defence response when signalling proteins bind to the tagged microbe. This triggers the formation of a double-membraned organelle called an autophagosome, which envelops the bacterium3,4. The autophagosome then fuses with the destruction machinery — an organelle called the lysosome5,6. Many of the steps in this process are understood, but the contributors to the initial step, the bacterial molecule modified by ubiquitin and the enzyme that directly marks Salmonella, were previously unknown.
Ubiquitin is typically joined to target proteins through covalent links to amino (and, in rare cases, hydroxyl) groups on proteins. These ubiquitylation reactions are catalysed by what are termed E3 ligase enzymes. Indeed, many bacterial and host proteins are ubiquitylated during infection by Salmonella7. Various E3 ligases have been proposed as having a role in combating Salmonella5. Unexpectedly, however, Otten and colleagues reveal not only that the ubiquitylation of Salmonella is catalysed by a different mechanism from that used by a classic E3 ligase, but also that the ubiquitylation target itself is not even a protein.
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