Butyrophilins (BTN) belong to the immunoglobulin (Ig) superfamily of transmembrane proteins. These molecules are of increasing interest to immunologists, as they share a structural homology with B7 family members at the extracellular domain level. Moreover, a role of these molecules has been suggested in the negative regulation of lymphocyte activation for almost all the BTN that have been studied. In addition, the expression of some BTN family members has been reported to be associated with autoimmune diseases. Over the last few years, the number of BTN and BTN-like members has greatly increased. In this study, the butyrophilin family in mammals has been revisited, using phylogenetic analysis to identify all the family members and the phylogenetic relations among them, and to establish a standard nomenclature. Fourteen BTN groups were identified that are not all conserved between mammalian species. In addition, an overview of expression profiles and functional BTN data demonstrates that these molecules represent a new area of investigation for the design of future strategies in the modulation of the immune system.

Tight regulation of collagen fibril deposition in the extracellular matrix is essential for normal tissue homeostasis and repair, defects in which are associated with several degenerative or fibrotic disorders. A key regulatory step in collagen fibril assembly is the C-terminal proteolytic processing of soluble procollagen precursors. This step, carried out mainly by bone morphogenetic protein-1/tolloid-like proteinases, is itself subject to regulation by procollagen C-proteinase enhancer proteins (PCPEs) which can dramatically increase bone morphogenetic protein-1/tolloid-like proteinase activity, in a substrate-specific manner. Although it is known that this enhancing activity requires binding of PCPE to the procollagen C-propeptide trimer, identification of the precise binding site has so far remained elusive. Here, use of small-angle X-ray scattering provides structural data on this protein complex indicating that PCPE binds to the stalk region of the procollagen C-propeptide trimer, where the three polypeptide chains associate together, at the junction with the base region. This is supported by site-directed mutagenesis, which identifies two highly conserved, surface-exposed lysine residues in this region of the trimer that are essential for binding, thus revealing structural parallels with the interactions of Complement C1r/C1s, Uegf, BMP-1 (CUB) domain-containing proteins in diverse biological systems such as complement activation, receptor signaling, and transport. Together with detailed kinetics and interaction analysis, these results provide insights into the mechanism of action of PCPEs and suggest clear strategies for the development of novel antifibrotic therapies.proteolysis | structural proteins | fibrosis R egulation of collagen deposition in the extracellular matrix is essential for normal tissue homeostasis and repair, defects in which are associated with numerous, often lethal, disorders, including chronic wounds and the many different forms of fibrosis (affecting heart, lung, liver, kidney, skin, etc.) (1, 2). At the protein level, a key regulatory step is the proteolytic conversion of soluble precursor molecules, procollagens, by removal of N-and C-propeptides (3), resulting in spontaneous assembly of collagen fibrils. Although collagen deposition in vivo is also controlled by numerous interactions with cell-surface and extracellular matrix proteins (4, 5), it is generally acknowledged that a key ratelimiting step is the proteolytic removal of the procollagen Cpropeptides. The principal proteinases involved here are zinc metalloproteinases, called bone morphogenetic protein-1 (BMP-1)/tolloid-like proteinases (collectively known as BTPs), which cleave the C-propeptides from the major fibrillar procollagens (types I, II, and III) (3,(6)(7)(8).Although BTPs cleave a number of extracellular substrates (including structural proproteins, proenzymes, and latent growth factors or their antagonists) (8, 9), their activity on fibrillar procollagens is specifically increased, several-fold, by procollag...

The butyrophilin 3 (BTN3) are receptors of the immunoglobulin superfamily implicated in the T lymphocytes regulation and present a wide plasticity in mammals, being absent in rodent but present with three copies in human. In order to understand how these genes have been diversified and what forces guiding this diversification, we studied their evolution and show that the three human BTN3 genes are the result of two successive duplications in Primates and that the three genes are present in Hominoids and the Old World Monkey groups. A thorough phylogenetic analysis reveals a concerted evolution of BTN3 characterized by a strong and recurrent homogenization of the region encoding the signal peptide and the IgV domain in Hominoids. During these homogenizations the sequences of BTN3A1 or BTN3A3 are replaced by BTN3A2 sequence. In human, the analysis of the diversity of the three genes in 1683 individuals representing 26 worldwide populations shows that the three genes are polymorphic, with more than 46 alleles for each gene, but they are also marked by extreme homogenization of the IgV sequences. The same analysis performed for the BTN2 genes that are also diversified in Primates, shows also a concerted evolution, however it is not as strong and recurrent as for BTN3. This study shows that BTN3 receptors are marked by extreme concerted evolution at the IgV domain and that BTN3A2 plays a central role in this evolution.

Among the genes with the highest allelic polymorphism and sequence diversity are those encoding the classical class I and class II molecules of the major histocompatibility complex (MHC). Although many thousands of MHC sequences have been deposited in general sequence databases like GenBank, the availability of curated MHC sequences with agreed nomenclature has been enormously beneficial. Along with the Immuno Polymorphism Database-IMunoGeneTics/human leukocyte antigen (IPD-IMGT/HLA) database, a collection of databases for curated sequences of immune importance has been developed. A recent addition is an IPD-MHC database for chickens. For many years, the nomenclature system for chicken MHC genes has been based on a list of standard, presumed to be stable, haplotypes. However, these standard haplotypes give different names to identical sequences. Moreover, the discovery of new recombinants between haplotypes and a rapid increase in newly discovered alleles leaves the old system untenable. In this review, a new nomenclature is considered, for which alleles of different loci are given names based on the system used for other MHCs, and then haplotypes are named according to the alleles present. The new nomenclature system is trialled, first with standard haplotypes and then with validated sequences from the scientific literature. In the trial, some class II B sequences were found in both class II loci, presumably by gene conversion or inversion, so that identical sequences would receive different names. This situation prompts further suggestions to the new nomenclature system. In summary, there has been progress, but also problems, with the new IPD-MHC system for chickens.

No abstract