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Four Reasons to Consider a Novel Class of Innate Immune Molecules in the Oral Epithelium

E.E. LeClair

Department of Biological Sciences, DePaul University, 2325 N. Clifton Ave., Chicago, IL 60614, USA; eleclair{at}depaul.edu



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Figure 1. Gene and protein structures of the human PLUNCs (Bingle and Bingle, 2000; Bingle and Craven, 2002). (A) Human PLUNC genes are located on chromosome 20. In mice, the corresponding gene cluster is on chromosome 2 (LeClair et al., 2001). (B) At least seven human PLUNC genes have been described. One system names the genes for the length of their protein products: three "short PLUNCs" (SPLUNC-1, -2, and -3; ~ 250 amino acids) and four "long PLUNCs" (LPLUNC-1, -2, -3, and -4; ~ 480 amino acids). Some of these sequences have also been published under other names (see Table 1Go). (C) The best-studied gene, SPLUNC-1 (also known as h-PLUNC, LUNX, or SPURT), has nine exons whose size and spacing are conserved in other short members of this family. A common factor is that the first exon contains a signal sequence for protein secretion. (D) PLUNC proteins have a predicted fold similar to that of bactericidal/permeability-increasing protein (BPI), shown as a ribbon diagram. Gray arrows indicate the BPI’s axis of symmetry between its barrel-shaped N and C-terminal domains. The "short" PLUNCS correspond in structure to the BPI N-terminus. "Long" PLUNCs have both the N- and C-terminal domains. Dark areas indicate regions of the peptide chain where the seven human PLUNCs diverge most from BPI (at the N-terminus and central hinge). Light areas show regions of greatest similarity between the two protein structures (in the barrel-shaped domains) (C.D. Bingle, unpublished data).

 


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Figure 2. Elements of the innate immune system that detect bacterial lipopolysaccharides (LPS; for review, see Triantafilou and Triantafilou, 2002; Weiss, 2003). LBP and BPI are similar lipophilic molecules that act as antagonists in the immune response to Gram-negative bacteria. (1) LBP binds to LPS and ferries it to a cell-surface receptor complex including CD14 and Toll-like receptors (TLRs). This stimulates the receiving cell to mount an immune response. (2) BPI acts as an antagonist to LBP, removing LPS from LBP interactions. (3) BPI also facilitates the transfer of LPS to phagocytic cells, where it is degraded. At least seven PLUNC proteins are predicted in humans. They have structural similarities to BPI and may act along similar pathways. Most interactions are speculative, as shown by dotted lines. (4) Like LBP, long PLUNC proteins could bind microbial molecules and present them to epithelial or immune cells. (5) Short PLUNC proteins from this multi-gene family could antagonize these signaling pathways, sequestering microbial molecules from immune detection. (6) Finally, like BPI, long PLUNC proteins could accelerate clearance of microbial molecules from the epithelial environment.

 





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