title: The ubiquitin-like modifier FAT10 decorates autophagy-targeted Salmonella and contributes to Salmonella resistance in mice.
abstract: Bacterial invasion of eukaryotic cells is counteracted by cell-autonomous innate immune mechanisms including xenophagy. The decoration of cytosolic bacteria by ubiquitylation and binding of galectin-8 leads to recruitment of autophagy adaptors like p62 (also known as SQSTM1), NDP52 (also known as CALCOCO2) and optineurin, which initiate the destruction of bacteria by xenophagy. Here, we show that the functionally barely characterized IFNγ- and TNFα-inducible ubiquitin-like modifier FAT10 (also known as ubiquitin D, UBD), which binds to the autophagy adaptor p62, but has not been shown to associate with pathogens before, is recruited to cytosolic Salmonella Typhimurium in human cells. FAT10-decorated S. Typhimurium were simultaneously decorated with ubiquitin, p62, NDP52 and the autophagy marker LC3B (MAP1LC3B). FAT10 colocalized with p62-positive microdomains on S. Typhimurium, whereas colocalization with NDP52 was only partial. A kinetic analysis revealed an early, but only transient, decoration of bacteria by FAT10, which resembled that of p62. Although bacterial replication was not detectably altered in FAT10-depleted or overexpressing cells in vitro, survival experiments revealed that NRAMP1-transgenic mice that were FAT10-deficient had a higher susceptibility to orally inoculated S. Typhimurium bacteria than NRAMP1-transgenic mice that were wild-type for FAT10. Taken together, our data suggest a role for FAT10 in the intracellular defense against bacteria.
authors.affiliation: Division of Immunology, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany.
authors.forename: Valentina
authors.initials: V
authors.lastname: Spinnenhirn
authors.affiliation: Focal Area Infection Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Hesso
authors.initials: H
authors.lastname: Farhan
authors.affiliation: Division of Immunology, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany Biotechnology Institute Thurgau at the University of Konstanz, CH-8280 Kreuzlingen, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Basler
authors.affiliation: Biotechnology Institute Thurgau at the University of Konstanz, CH-8280 Kreuzlingen, Switzerland.
authors.forename: Annette
authors.initials: A
authors.lastname: Aichem
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Allon
authors.initials: A
authors.lastname: Canaan
authors.affiliation: Division of Immunology, Department of Biology, University of Konstanz, D-78457 Konstanz, Germany Biotechnology Institute Thurgau at the University of Konstanz, CH-8280 Kreuzlingen, Switzerland Marcus.Groettrup@uni-konstanz.de.
authors.forename: Marcus
authors.initials: M
authors.lastname: Groettrup
mesh_terms: D000818:Animals; D001343:Autophagy; D057809:HEK293 Cells; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012486:Salmonella typhimurium / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: C512253:FAT10 protein, mouse; C109184:UBD protein, human; D025801:Ubiquitin; D014452:Ubiquitins
keywords: Autophagy; FAT10; Salmonella Typhimurium; Ubiquitin; Xenophagy; p62