期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 37, 页码 13469-13474出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1405414111
关键词
pattern recognition receptor; immune response; NF-kappa B signaling pathway
资金
- Major National Scientific Research Project [2013CB917800]
- National Basic Research Program (973) [2013CB835300]
- State High-Tech Development Project (863) [2008AA092601, 2012AA092201]
- National Natural Science Foundation [91231206, 30730089, 31171193, 30901305]
- Commission of Science and Technology of Guangdong Province
- Guangzhou City
- Sun Yat-sen University Science Foundation
- Guangdong Province Key Laboratory of Computational Science
- Guangdong Province Computational Science Innovative Research Team
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 Grampositive 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-.B activation. MDP was found to compete with TRAF6 for bjALP2, which released TRAF6 to activate the NF-.B 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.
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