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A sweet way of sensing danger

Cells can destroy invading bacteria through a digestive process called autophagy. A study finds that sugar molecules, exposed by bacterial damage to the cell's membrane, can trigger this process. See Letter p.414

The bacterium Salmonella enterica serovar Typhimurium is a leading cause of food poisoning and a well-studied model pathogen. On ingestion by its host, the microbe can penetrate and grow in the gut's epithelial cells, and damage cell membranes. These events can lead to inflammation and to the pathogen's spread to other tissues. To combat the infection, one defence mechanism available to cells is autophagy — a process by which the intracellular bacteria are digested in cytoplasmic vesicles known as lysosomes. On page 414 of this issue, Thurston et al.1 report that sugar molecules normally present on the cell's surface can act as a 'danger' signal in the cytoplasm to target S. Typhimurium for autophagy.

Autophagy is a highly regulated process, during which cytoplasmic cargoes are captured in a double-membrane vesicle, the autophagosome. This vesicle then fuses with lysosomes, which are loaded with digestive enzymes that eventually degrade the vesicle's contents. Cells use autophagy to maintain a balance between the synthesis and degradation of their own components, and malfunction of the process has been linked to human diseases such as cancer, neurodegenerative disorders, diabetes and inflammatory bowel disease. The autophagy system can also target invading pathogens such as S. Typhimurium for degradation, although the precise mechanisms underlying this process are not well understood.

Early after cell invasion, S. Typhimurium resides in a vesicle known as the Salmonella-containing vacuole (SCV). Some of the bacteria then use specialized protein machinery (called a type III secretion system)2 to generate pores in the SCV membrane, through which they deliver protein effectors into the cell's cytoplasm. The effectors modulate the activity of the host's cellular machinery to promote intracellular growth of the pathogen. Moreover, damaged SCVs allow some of the bacteria to escape and replicate in the cytosol. However, the microbes in damaged vesicles can also 'attract' components of the autophagy machinery, such as the protein LC3, as well as autophagosomes that engulf the damaged SCVs and restrict bacterial growth2,3 (Fig. 1).

Figure 1: Broken vesicles as danger signals.

a, b, Early after the pathogenic bacterium S. Typhimurium invades host cells (a), it resides in a cytoplasmic vesicle known as a Salmonella-containing vacuole (SCV; b). c, The bacterium can damage the vacuole membrane, exposing host sugar molecules to the cytoplasm. Thurston et al.1 report that the host protein galectin 8 binds to these sugars and triggers a process called autophagy, by which the invading bacteria are destroyed. Specifically, the authors found that galectin 8 recruits another protein, NDP52, by direct interaction. NDP52, in turn, binds to the protein LC3 and recruits other components of the autophagy machinery to the damaged SCV. d, Eventually, the bacterium is enclosed in a specialized vesicle known as an autophagosome, which forms from the isolation membrane. e, Other vesicles (lysosomes) containing digestive enzymes can then fuse with the autophagosome, forming the autolysosome within which the pathogen is destroyed. f, The authors found that osmotic damage to cytoplasmic vesicles, in the absence of bacteria, also exposes host sugars that recruit galectin 8.

So how does the autophagy system recognize the bacteria in damaged SCVs? Host factors such as reactive oxygen species4 and the lipid diacylglycerol5 play a part in the recruitment of LC3 to SCVs. In addition, the microbes attract the protein ubiquitin, which seems to recruit autophagy 'adaptor' proteins that, in turn, bind to LC3. In particular, the adaptor proteins p62, NDP52 and optineurin contribute to LC3 recruitment to the bacteria6,7,8. However, these adaptors are not functionally redundant — depletion of any of them impairs antibacterial autophagy — and they bind to different regions, or microdomains, around an individual bacterium9. These observations suggest that there may be different signature molecules on the microbial surface and/or on the damaged SCV that attract different adaptor proteins, and that SCV damage is essential to exposing these signature molecules.

To explore potential mechanisms of adaptor recruitment, Thurston et al.1 focused on galectins, a family of proteins that bind complex sugar molecules. The authors found that, 1 hour after invasion by S. Typhimurium, galectins were associated with a small population of the bacteria in the host cells. When they abolished the expression of a specific galectin, galectin 8, intracellular bacteria grew at an increased rate. Furthermore, galectin 8 co-localized with NDP52 on the intracellular microbes, although at microdomains distinct from those to which p62 or ubiquitin bind.

Thurston and colleagues carried out experiments with live cells and purified proteins that confirmed a direct interaction between galectin 8 and NDP52. Moreover, the authors observed that cells lacking galectin 8 failed to recruit NDP52 to the bacteria at 1 hour after invasion, suggesting that galectin 8 acts as an early signal to attract autophagy adaptors. The recruitment of LC3 to the intracellular microbes was also significantly reduced. When the authors artificially targeted NDP52 to SCVs in the galectin-8-depleted cells, bacterial growth was again restricted. This indicates that galectin-8 recruitment of NDP52 is essential for the induction of antibacterial autophagy.

But how do the intracellular bacteria attract the sugar-binding galectin? SCV damage exposes the cytoplasm to different sugar molecules. Although some of these derive from the bacteria, there are also host molecules that were initially present in the vesicle. Thurston et al.1 report that purified galectin 8 does not bind to S. Typhimurium in vitro, which suggests that the molecule targeted by galectin 8 is not derived from the microbe. Furthermore, the targeting of galectin 8 to intracellular S. Typhimurium was severely impaired in host cells lacking complex sugar molecules, which are normally found on the cell's surface and lining the inside of some vesicles. The authors found that other vesicle-damaging pathogenic bacteria such as Listeria monocytogenes and Shigella flexneri are also decorated by galectins soon after infection. Moreover, osmotic damage of cytoplasmic vesicles in the absence of bacteria also resulted in the recruitment of galectins to the damaged vesicles. On the basis of their observations, the researchers conclude that galectins can act as sensors of non-specific danger by detecting host sugar molecules that are exposed on damaged vesicle membranes.

Although it has been speculated2 that damaged SCVs serve as a signal to target bacteria for autophagy, Thurston and colleagues' work provides much-needed insight into the mechanistic details. Their results show that, when the microbes try to escape into the cytoplasm by disrupting the vesicles, host sugar molecules are exposed. Cytoplasmic galectin 8 then functions as a danger receptor: it binds to the exposed carbohydrates and recruits NDP52, which further attracts LC3 and autophagy machinery to the damaged compartment, thus triggering antibacterial autophagy soon after infection.

But the authors also show that recruitment of galectin 8 to damaged vesicles is a general danger response. Whether autophagy is also activated by galectin 8 in any other situations in which a cellular organelle is disrupted needs to be further investigated. Other galectins are recruited to damaged cytoplasmic vesicles such as SCVs, but at present their role in cellular defences to infection is unclear.

Is sugar exposure the only signal required to detect damaged SCVs? Most likely not, because NDP52 is only one of the three adaptors required to target S. Typhimurium to autophagy. So, the mechanisms that regulate recruitment of p62 and optineurin to damaged SCVs, and the ways by which the three adaptors cooperatively regulate antimicrobial autophagy, are exciting questions for future studies.


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Correspondence to Ju Huang or John H. Brumell.

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Huang, J., Brumell, J. A sweet way of sensing danger. Nature 482, 316–317 (2012).

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