Publication Date:
2013-11-22
Description:
Human body-surface epithelia coexist in close association with complex bacterial communities and are protected by a variety of antibacterial proteins. C-type lectins of the RegIII family are bactericidal proteins that limit direct contact between bacteria and the intestinal epithelium and thus promote tolerance to the intestinal microbiota. RegIII lectins recognize their bacterial targets by binding peptidoglycan carbohydrate, but the mechanism by which they kill bacteria is unknown. Here we elucidate the mechanistic basis for RegIII bactericidal activity. We show that human RegIIIalpha (also known as HIP/PAP) binds membrane phospholipids and kills bacteria by forming a hexameric membrane-permeabilizing oligomeric pore. We derive a three-dimensional model of the RegIIIalpha pore by docking the RegIIIalpha crystal structure into a cryo-electron microscopic map of the pore complex, and show that the model accords with experimentally determined properties of the pore. Lipopolysaccharide inhibits RegIIIalpha pore-forming activity, explaining why RegIIIalpha is bactericidal for Gram-positive but not Gram-negative bacteria. Our findings identify C-type lectins as mediators of membrane attack in the mucosal immune system, and provide detailed insight into an antibacterial mechanism that promotes mutualism with the resident microbiota.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160023/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160023/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mukherjee, Sohini -- Zheng, Hui -- Derebe, Mehabaw G -- Callenberg, Keith M -- Partch, Carrie L -- Rollins, Darcy -- Propheter, Daniel C -- Rizo, Josep -- Grabe, Michael -- Jiang, Qiu-Xing -- Hooper, Lora V -- C06 RR30414/RR/NCRR NIH HHS/ -- F32 DK100074/DK/NIDDK NIH HHS/ -- GM093271/GM/NIGMS NIH HHS/ -- R01 DK070855/DK/NIDDK NIH HHS/ -- R01 NS040944/NS/NINDS NIH HHS/ -- R01 NS40944/NS/NINDS NIH HHS/ -- R01GM088745/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jan 2;505(7481):103-7. doi: 10.1038/nature12729. Epub 2013 Nov 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Biological Sciences, University of Pittsburgh, and Joint Carnegie Mellon University-University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, Pennsylvania 15261, USA. ; Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, USA. ; Department of Biochemistry and Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Biological Sciences, University of Pittsburgh, and Joint Carnegie Mellon University-University of Pittsburgh PhD Program in Computational Biology, Pittsburgh, Pennsylvania 15261, USA [2] Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94143, USA. ; 1] Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2]. ; 1] Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] The Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24256734" target="_blank"〉PubMed〈/a〉
Keywords:
Anti-Bacterial Agents/chemistry/immunology/*metabolism/pharmacology
;
Antigens, Neoplasm/chemistry/immunology/*metabolism
;
Biomarkers, Tumor/antagonists & inhibitors/chemistry/immunology/*metabolism
;
Cell Membrane Permeability/drug effects
;
Cryoelectron Microscopy
;
Crystallography, X-Ray
;
Gram-Negative Bacteria/drug effects/immunology/metabolism
;
Humans
;
Immunity, Mucosal/drug effects/immunology
;
Intestines/*chemistry/immunology/microbiology
;
Lectins, C-Type/antagonists & inhibitors/chemistry/immunology/*metabolism
;
Lipopolysaccharides/pharmacology
;
Listeria monocytogenes/drug effects/immunology/metabolism
;
Microbial Viability/drug effects
;
Models, Molecular
;
Peptidoglycan/metabolism
;
Phospholipids/metabolism
;
Porins/antagonists & inhibitors/chemistry/*metabolism
;
Symbiosis
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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