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1.C.111 The RegIIIγ (RegIIIγ) Family

The mammalian intestine is home to ~100 trillion bacteria that perform important metabolic functions for their hosts. The proximity of vast numbers of bacteria to host intestinal tissues raises the question of how symbiotic host-bacterial relationships are maintained without eliciting potentially harmful immune responses. Here, we show that RegIIIγ, a secreted antibacterial lectin, is essential for maintaining a ~50-micrometer zone that physically separates the microbiota from the small intestinal epithelial surface. Loss of host-bacterial segregation in RegIIIγ(-/-) mice was coupled to increased bacterial colonization of the intestinal epithelial surface and enhanced activation of intestinal adaptive immune responses by the microbiota. Together, our findings reveal that RegIIIγ is a fundamental immune mechanism that promotes host-bacterial mutualism by regulating the spatial relationships between microbiota and host. The mammalian intestine harbors complex societies of beneficial bacteria that are maintained in the lumen with minimal penetration of mucosal surfaces. Microbial colonization of germ-free mice triggers epithelial expression of RegIIIγ which binds intestinal bacteria but lacks the complement recruitment domains present in other microbe-binding mammalian C-type lectins. Cash et al. (2006b) showed that RegIIIγ and its human counterpart, HIP/PAP, are direct antimicrobial proteins that bind their bacterial targets via interactions with peptidoglycan carbohydrate. They proposed that these proteins represent an evolutionarily primitive form of lectin-mediated innate immunity, and that they reveal intestinal strategies for maintaining symbiotic host-microbial relationships. Electron microscopic studies suggested that the protein inserts into the membrane and forms multimeric pores (Cash et al., 2006b; Cash et al., 2006).

The mammalian intestine is home to ~100 trillion bacteria that perform important metabolic functions for their hosts. The proximity of vast numbers of bacteria to host intestinal tissues raises the question of how symbiotic host-bacterial relationships are maintained without eliciting potentially harmful immune responses. Li et al. (2011) showed that RegIIIγ maintains a ~50-micrometer zone that physically separates the microbiota from the small intestinal epithelial surface. Loss of host-bacterial segregation in RegIIIγ(-/-) mice was coupled to increased bacterial colonization of the intestinal epithelial surface and enhanced activation of intestinal adaptive immune responses by the microbiota. Thus, RegIIIγ provides a fundamental immune mechanism that promotes host-bacterial mutualism by regulating the spatial relationships between microbiota and host.

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. Mukherjee et al. (2014) elucidated the mechanistic basis for RegIII bactericidal activity and showed that human RegIIIα (also known as HIP/PAP) binds membrane phospholipids and kills bacteria by forming a hexameric membrane-permeabilizing oligomeric pore. They derived a three-dimensional model of the RegIIIα pore by docking the RegIIIα crystal structure into a cryo-electron microscopic map of the pore complex, and showed that the model accords with experimentally determined properties of the pore. Lipopolysaccharide inhibits RegIIIα pore-forming activity, explaining why RegIIIα is bactericidal for Gram-positive but not Gram-negative bacteria. Their findings identified C-type lectins as mediators of membrane attack in the mucosal immune system and provided insight into an antibacterial mechanism that promotes mutualism with the resident microbiota (Cash et al., 2006b).

The mammalian intestine is home to ~100 trillion bacteria that perform important metabolic functions for their hosts. The proximity of vast numbers of bacteria to host intestinal tissues raises the question of how symbiotic host-bacterial relationships are maintained without eliciting potentially harmful immune responses. Li et al. (2011) showed that RegIIIγ maintains a ~50-micrometer zone that physically separates the microbiota from the small intestinal epithelial surface. Loss of host-bacterial segregation in RegIIIγ(-/-) mice was coupled to increased bacterial colonization of the intestinal epithelial surface and enhanced activation of intestinal adaptive immune responses by the microbiota. Thus, RegIIIγ provides a fundamental immune mechanism that promotes host-bacterial mutualism by regulating the spatial relationships between microbiota and host.

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. Mukherjee et al. (2014) elucidated the mechanistic basis for RegIII bactericidal activity and showed that human RegIIIα (also known as HIP/PAP) binds membrane phospholipids and kills bacteria by forming a hexameric membrane-permeabilizing oligomeric pore. They derived a three-dimensional model of the RegIIIα pore by docking the RegIIIα crystal structure into a cryo-electron microscopic map of the pore complex, and showed that the model accords with experimentally determined properties of the pore. Lipopolysaccharide inhibits RegIIIα pore-forming activity, explaining why RegIIIα is bactericidal for Gram-positive but not Gram-negative bacteria. Their findings identified C-type lectins as mediators of membrane attack in the mucosal immune system and provided insight into an antibacterial mechanism that promotes mutualism with the resident microbiota (Mukherjee et al. 2014).

 

References associated with 1.C.111 family:

Cash, H.L., C.V. Whitham, and L.V. Hooper. (2006). Refolding, purification, and characterization of human and murine RegIII proteins expressed in Escherichia coli. Protein Expr Purif 48: 151-159. 16504538
Cash, H.L., C.V. Whitham, C.L. Behrendt, and L.V. Hooper. (2006). Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313: 1126-1130. 16931762
Mukherjee, S., H. Zheng, M.G. Derebe, K.M. Callenberg, C.L. Partch, D. Rollins, D.C. Propheter, J. Rizo, M. Grabe, Q.X. Jiang, and L.V. Hooper. (2014). Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature 505: 103-107. 24256734