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Autophagy defends the mammalian cytosol against bacterial infection1- 3. Efficient pathogen engulfment ismediated by cargo-selecting autophagy adaptors that rely on unidentified pattern-recognition or danger receptors to label invading pathogens as autophagy cargo, typically by polyubiquitin coating4-9. Here we show in human cells that galectin 8 (also known as LGALS8), a cytosolic lectin, is a danger receptor that restricts Salmonella proliferation. Galectin 8 monitors endosomal and lysosomal integrity and detects bacterial invasion by binding host glycans exposed on damaged Salmonella-containing vacuoles. By recruiting NDP52 (also known as CALCOCO2), galectin 8 activates antibacterial autophagy. Galectin-8-dependent recruitment ofNDP52 to Salmonella-containing vesicles is transient and followed by ubiquitin-dependent NDP52 recruitment. Because galectin 8 also detects sterile damage to endosomes or lysosomes, as well as invasion by Listeria or Shigella, we suggest that galectin 8 serves as a versatile receptor for vesicle-damaging pathogens. Our results illustrate how cells deploy the danger receptor galectin 8 to combat infection bymonitoring endosomal and lysosomal integrity on the basis of the specific lack of complex carbohydrates in the cytosol.
Galectins are b-galactoside-binding lectins that accumulate in the cytosol before being secreted via a leader-peptide-independent pathway10,11. The best-characterized functions of galectins are performed extracellularly, where they bind glycans to modulate cellular behaviour. However, the occurrence of galectins in the cytosol, which under physiological conditions is devoid of complex carbohydrates, makes them prime candidates for a role as danger and/or pattern-recognition receptors.Galectin 3 (also knownasLGALS3) accumulates on damaged bacteria-containing vesicles, although the functional consequences of its recruitment remain unknown12,13. We screened a panel of human galectins for their ability to detect invasion by Salmonella enterica serovar Typhimurium. At 1 h post-infection (p.i.), galectin 3, 8 and 9 accumulated on about 10% of intracellular S. Typhimurium (Fig. 1a, b and Supplementary Fig. 1a), ofwhich 90%were associated withLAMP1 (Supplementary Fig. 1b). Recruitment of galectins peaked between 1 h and 2 h p.i. (Supplementary Fig. 1c). As galectin 3, 8 and 9 were recruited to Salmonella-containing vesicles (SCVs), we used short interfering RNAs (siRNAs) to test whether their depletion causes hyperproliferation of S.Typhimurium. Cells lacking galectin 8 orNDP52, but not galectin 3 and/or 9, failed to suppress proliferation of S. Typhimurium (Fig. 1c and Supplementary Figs 2a-c and 3a). Microscopic analysis confirmed that the greater bacterial burden of cells...