Human α-defensin 6 promotes mucosal innate immunity through self-assembled peptide nanonets.
Defensins are antimicrobial peptides that contribute broadly to innate immunity, including protection of mucosal tissues. Human α-defensin (HD) 6 is highly expressed by secretory Paneth cells of the small intestine. However, in contrast to the other defensins, it lacks appreciable bactericidal activity. Nevertheless, we report here that HD6 affords protection against invasion by enteric bacterial pathogens in vitro and in vivo. After stochastic binding to bacterial surface proteins, HD6 undergoes ordered self-assembly to form fibrils and nanonets that surround and entangle bacteria. This self-assembly mechanism occurs in vivo, requires histidine-27, and is consistent with x-ray crystallography data. These findings support a key role for HD6 in protecting the small intestine against invasion by diverse enteric pathogens and may explain the conservation of HD6 throughout Hominidae evolution.
Department of Microbiology and Immunology, School of Medicine, University of California, Davis, CA 95616, USA.
Hiutung
H
Chu
Marzena
M
Pazgier
Grace
G
Jung
Sean-Paul
SP
Nuccio
Patricia A
PA
Castillo
Maarten F
MF
de Jong
Maria G
MG
Winter
Sebastian E
SE
Winter
Jan
J
Wehkamp
Bo
B
Shen
Nita H
NH
Salzman
Mark A
MA
Underwood
Renee M
RM
Tsolis
Glenn M
GM
Young
Wuyuan
W
Lu
Robert I
RI
Lehrer
Andreas J
AJ
Bäumler
Charles L
CL
Bevins
D018829:Adhesins, Bacterial / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology / Q000648:ultrastructure; D007421:Intestine, Small / Q000276:immunology* / Q000382:microbiology / Q000648:ultrastructure; D046911:Macromolecular Substances / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D008958:Models, Molecular; D049329:Nanostructures; D019879:Paneth Cells / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D012481:Salmonella Infections, Animal / Q000276:immunology / Q000382:microbiology; D012486:Salmonella typhimurium / Q000276:immunology / Q000472:pathogenicity / Q000648:ultrastructure; D015008:Yersinia enterocolitica / Q000276:immunology / Q000472:pathogenicity; D023084:alpha-Defensins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
D018829:Adhesins, Bacterial; D001426:Bacterial Proteins; C517765:DEFA6 protein, human; D046911:Macromolecular Substances; D010455:Peptides; D023084:alpha-Defensins; D054299:env Gene Products, Human Immunodeficiency Virus; C053476:invasin, Yersinia