title: Two apextrin-like proteins mediate extracellular and intracellular bacterial recognition in amphioxus.
abstract: Animals exploit different germ-line-encoded proteins with various domain structures to detect the signature molecules of pathogenic microbes. These molecules are known as pathogen-associated molecular patterns (PAMPs), and the host proteins that react with PAMPs are called pattern recognition proteins (PRPs). Here, we present a novel type of protein domain structure capable of binding to bacterial peptidoglycan (PGN) and the minimal PGN motif muramyl dipeptide (MDP). This domain is designated as apextrin C-terminal domain (ApeC), and its presence was confirmed in several invertebrate phyla and subphyla. Two apextrin-like proteins (ALP1 and ALP2) were identified in a basal chordate, the Japanese amphioxus Branchiostoma japonicum (bj). bjALP1 is a mucosal effector secreted into the gut lumen to agglutinate the Gram-positive bacterium Staphylococcus aureus via PGN binding. Neutralization of secreted bjALP1 by anti-bjALP1 monoclonal antibodies caused serious damage to the gut epithelium and rapid death of the animals after bacterial infection. bjALP2 is an intracellular PGN sensor that binds to TNF receptor-associated factor 6 (TRAF6) and prevents TRAF6 from self-ubiquitination and hence from NF-κB activation. MDP was found to compete with TRAF6 for bjALP2, which released TRAF6 to activate the NF-κB pathway. BjALP1 and bjALP2 therefore play distinct and complementary functions in amphioxus gut mucosal immunity. In conclusion, discovery of the ApeC domain and the functional analyses of amphioxus ALP1 and ALP2 allowed us to define a previously undocumented type of PRP that is represented across different animal phyla.
authors.affiliation: State Key Laboratory of Biocontrol, Open Laboratory for Marine Functional Genomics of the State High-Tech Development Program, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China; School of Basic Medical Sciences, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China; and Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Guangrui
authors.initials: G
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Biocontrol, Open Laboratory for Marine Functional Genomics of the State High-Tech Development Program, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China;
authors.forename: Shengfeng
authors.initials: S
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Biocontrol, Open Laboratory for Marine Functional Genomics of the State High-Tech Development Program, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China;
authors.forename: Xinyu
authors.initials: X
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Biocontrol, Open Laboratory for Marine Functional Genomics of the State High-Tech Development Program, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China;
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biocontrol, Open Laboratory for Marine Functional Genomics of the State High-Tech Development Program, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China;
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biocontrol, Open Laboratory for Marine Functional Genomics of the State High-Tech Development Program, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China;
authors.forename: Weiya
authors.initials: W
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Biocontrol, Open Laboratory for Marine Functional Genomics of the State High-Tech Development Program, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China;
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biocontrol, Open Laboratory for Marine Functional Genomics of the State High-Tech Development Program, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China;
authors.forename: Ruihua
authors.initials: R
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biocontrol, Open Laboratory for Marine Functional Genomics of the State High-Tech Development Program, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China;
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Biocontrol, Open Laboratory for Marine Functional Genomics of the State High-Tech Development Program, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China;
authors.forename: Shaochun
authors.initials: S
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Biocontrol, Open Laboratory for Marine Functional Genomics of the State High-Tech Development Program, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China;
authors.forename: Shangwu
authors.initials: S
authors.lastname: Chen
authors.affiliation: School of Basic Medical Sciences, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China; and Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Guangbin
authors.initials: G
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Biocontrol, Open Laboratory for Marine Functional Genomics of the State High-Tech Development Program, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, School of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China; School of Basic Medical Sciences, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China; and lssxal@mail.sysu.edu.cn.
authors.forename: Anlong
authors.initials: A
authors.lastname: Xu
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000371:Agglutination / Q000187:drug effects; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001419:Bacteria / Q000276:immunology*; D001424:Bacterial Infections / Q000276:immunology / Q000473:pathology; D005110:Extracellular Space / Q000382:microbiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000382:microbiology*; D064175:Lancelets / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology*; D008954:Models, Biological; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D010457:Peptidoglycan / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000648:ultrastructure; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D016328:NF-kappa B; D010457:Peptidoglycan; D011506:Proteins; D051192:Receptors, Pattern Recognition; D048029:TNF Receptor-Associated Factor 6; D000119:Acetylmuramyl-Alanyl-Isoglutamine
keywords: NF-κB signaling pathway; immune response; pattern recognition receptor