Summary
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 microbiota1,2. RegIII lectins
recognize their bacterial targets by binding peptidoglycan
carbohydrate1,3 but the mechanism by which they kill
bacteria is unknown. Here we elucidate the mechanistic basis for RegIII
bactericidal activity. Here we show that human RegIIIα
(hRegIIIα, 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 hRegIIIα pore by docking the
hRegIIIα 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 hRegIIIα
pore-forming activity, explaining why hRegIIIα 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.
The mammalian intestine is colonized by trillions of bacteria that perform essential metabolic functions for their hosts. The mutualistic nature of this relationship depends on maintaining spatial segregation between these bacteria and the intestinal epithelial surface. This segregation is achieved in part by the presence of a dense mucus layer at the epithelial surface and by the production of antimicrobial proteins that are secreted by epithelial cells into the mucus layer. Here, we show that resistin-like molecule β (RELMβ) is a bactericidal protein that limits contact between Gram-negative bacteria and the colonic epithelial surface. Mouse and human RELMβ selectively killed Gram-negative bacteria by forming size-selective pores that permeabilized bacterial membranes. In mice lacking RELMβ, Proteobacteria were present in the inner mucus layer and invaded mucosal tissues. Another RELM family member, human resistin, was also bactericidal, suggesting that bactericidal activity is a conserved function of the RELM family. Our findings thus identify the RELM family as a unique family of bactericidal proteins and show that RELMβ promotes host-bacterial mutualism by regulating the spatial segregation between the microbiota and the intestinal epithelium.antibacterial protein | microbiota | innate immunity | intestinal epithelium
Highlights d Skin microbiota induces epidermal RELMa, which kills bacteria via membrane disruption d RELMa-deficient mice have altered skin microbiota and are more susceptible to infection d Dietary vitamin A is required for RELMa expression d RELMa is required for vitamin-A-dependent resistance to skin infection
AMPlifying type 2 immunity
Antimicrobial proteins (AMPs) are a frontline defense against pathogenic microorganisms at mucosal surfaces. These cationic molecules inactivate their targets primarily by disrupting cell walls and membranes. Hu
et al
. found that small proline-rich protein 2A (SPRR2A) is a bactericidal protein produced in the gut that targets Gram-positive bacteria and is phylogenetically distinct from all other known AMPs (see the Perspective by Harris and Wickramasinghe). SPRR2A production is selectively enhanced by type 2 cytokines such as interleukin-4 and -13 that are elicited by helminth infection. Mice lacking SPRR2A are unable to prevent intestinal bacteria from invading the intestinal barrier after helminths damage the intestinal epithelium. SPRR2A is thus a critical component of type 2 immunity that protects against the bacterial invasion and dissemination that follow helminth infection. —STS
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.