Alternative titles; symbols
HGNC Approved Gene Symbol: NAIP
Cytogenetic location: 5q13.2 Genomic coordinates (GRCh38): 5:70,968,166-71,025,339 (from NCBI)
In a search for the gene causing spinal muscular atrophy (SMA; 253300), Roy et al. (1995) isolated a gene on chromosome 5q13.1, of which the first 2 coding exons were deleted in approximately 67% of type I SMA chromosomes compared with 2% of non-SMA chromosomes. One model of SMA pathogenesis invokes an inappropriate persistence of motor neuron apoptosis, which is a normally occurring phenomenon in development. Consistent with this hypothesis, the novel gene was labeled 'neuronal apoptosis inhibitory protein' (NAIP) and its function was supported by the finding that it contains domains with sequence similarity to IAPs, baculovirus proteins that inhibit virally induced insect cell apoptosis. The presence of a variable number of copies of truncated and internally deleted versions of the NAIP gene (pseudogenes) was thought to be a possible factor in the genesis of SMA. This situation was compared to that of the genes on 6p that code for steroid 21-hydroxylase (CYP21) deficiency (201910); through the processes of unequal crossing-over or gene conversion, mutations in the functional CYP21 gene (613815) can result. Roy et al. (1995) raised the possibility that NAIP functions in concert with SMN (600354) mutations in causing spinal muscular atrophy.
Liston et al. (1996) demonstrated that expression of NAIP in mammalian cells inhibits apoptosis induced by a variety of signals.
NAIP, HIAP1 (601721), HIAP2 (601712), XIAP (300079), BIRC5 (603352), and BIRC6 (605638) are members of the mammalian inhibitors of apoptosis family and contain an N-terminal domain with 1 to 3 imperfect repeats of an approximately 65-amino acid domain named the baculovirus IAP repeat (BIR) motif. Gotz et al. (2000) identified 6 mouse Naip genes which were expressed in a broad range of tissues. Using a neurite outgrowth assay in rat pheochromocytoma PC12 cells, they observed that Naip overexpression impaired nerve growth factor (NGF)-induced neurite outgrowth. The BIR motifs of Naip (residues 1-345) were not required for this effect. However, the BIR domains of Naip were essential to prevent apoptosis in PC12 cells after NGF deprivation or tumor necrosis factor-alpha receptor (TNFAR; 191190) stimulation. Expression of full-length but not BIR-deleted Naip protected against cell death. This correlated with reduced activity of the cell death effector protease, caspase-3 (600636), in lysates of Naip-PC12 cells. The authors hypothesized that dysregulation of cellular differentiation and/or caspase suppression may contribute to motoneuron dysfunction and cell death in spinal muscular atrophy where NAIP is mutated.
Kofoed and Vance (2011) showed in mice that different NAIP paralogs determine the specificity of the NLRC4 (606831) inflammasome for distinct bacterial ligands. In particular, they found that activation of endogenous NLRC4 by bacterial PrgJ requires NAIP2, a previously uncharacterized member of the NAIP gene family, whereas NAIP5 and NAIP6 activate NLRC4 specifically in response to bacterial flagellin. Kofoed and Vance (2011) dissected the biochemical mechanism underlying the requirement for NAIP proteins by use of a reconstituted NLRC4 inflammasome system. They found that NAIP proteins control ligand-dependent oligomerization of NLRC4 and that the NAIP2-NLRC4 complex physically associates with PrgJ but not flagellin, whereas NAIP5-NLRC4 associates with flagellin but not PrgJ. Kofoed and Vance (2011) concluded that their results identified NAIPs as immune sensor proteins in the mouse and provided biochemical evidence for a simple receptor-ligand model for activation of the NAIP-NLRC4 inflammasomes.
Zhao et al. (2011) showed that NAIP5, required for Legionella pneumophila replication in mouse macrophages, is a universal component of the flagellin-NLCR4 pathway. NAIP5 directly and specifically interacted with flagellin, which determined the inflammasome stimulation activities of different bacterial flagellins. NAIP5 engagement by flagellin promoted a physical NAIP5-NLRC4 association, rendering full reconstitution of a flagellin-responsive NLRC4 inflammasome in nonmacrophage cells. The related NAIP2 functioned analogously to NAIP5, serving as a specific inflammasome receptor for type III secretion system (TTSS) rod proteins such as Salmonella PrgJ and Burkholderia BsaK. Genetic analysis of Chromobacterium violaceum infection revealed that the TTSS needle protein Cpr1 can stimulate NLRC4 inflammasome activation in human macrophages. Similarly, Cpr1 is specifically recognized by human NAIP, the sole NAIP family member in human. The finding that NAIP proteins are inflammasome receptors for bacterial flagellin and TTSS apparatus components further predicted that the remaining NAIP family members may recognize other microbial products to activate NLRC4 inflammasome-mediated innate immunity.
To identify CASP1 (147678) functions in vivo, von Moltke et al. (2012) devised a strategy for cytosolic delivery of bacterial flagellin, a specific ligand for the NAIP5/NLRC4 inflammasome. Von Moltke et al. (2012) showed that systemic inflammasome activation by flagellin leads to a loss of vascular fluid into the intestine and peritoneal cavity, resulting in rapid (less than 30 minutes) death in mice. This unexpected response depends on the inflammasome components NAIP5, NLRC4, and CASP1, but is independent of the production of IL1-beta (147720) or IL18 (600953). Instead, inflammasome activation results, within minutes, in an 'eicosanoid storm'--a pathologic release of signaling lipids, including prostaglandins and leukotrienes, that rapidly initiate inflammation and vascular fluid loss. Mice deficient in cyclooxygenase-1 (COX1, PTGS1; 176805), a critical enzyme in prostaglandin biosynthesis, are resistant to these rapid pathologic effects of systemic inflammasome activation by either flagellin or anthrax lethal toxin. Inflammasome-dependent biosynthesis of eicosanoids is mediated by the activation of cytosolic phospholipase A2 (see 172410) in resident peritoneal macrophages, which are specifically primed for the production of eicosanoids by high expression of eicosanoid biosynthetic enzymes. Von Moltke et al. (2012) concluded that their results identified eicosanoids as a previously unrecognized cell type-specific signaling output of the inflammasome with marked physiologic consequences in vivo.
Karki et al. (2018) found that Irf8 (601565) was required for optimal Nlrc4 (606831) inflammasome activation, but not Aim2 (604578), Nlrp3 (606416), or pyrin (MEFV; 608107) inflammasome activation, during bacterial infection in mouse bone marrow-derived macrophages (BMDMs). Nlrc4 inflammasome activation by Irf8 was dependent on functional type III secretion system (T3SS) proteins encoded by pathogenicity island-1 (SPI-1) of bacteria. Furthermore, Irf8 regulated expression of critical components of the Nlrc4 inflammasome complex, including NAIPs, at the transcriptional level by binding directly to their promoters. Irf8 -/- mice were susceptible to bacterial infection, indicating that Irf8 is a critical regulator of NAIPs and NLRC4 inflammasome activation for defense against bacterial infection.
Roy et al. (1995) mapped the NAIP gene to chromosome 5q13.1. DiDonato et al. (1997) mapped the mouse homolog of NAIP to chromosome 13 in a region showing conserved synteny with human 5q13.
Although NAIP deletions are more frequently observed in patients affected by the acute form of SMA, it is not possible to establish an unambiguous correlation between deletion size and clinical severity. Novelli et al. (1997) investigated the effects of gender on the association between NAIP gene deletion and disease severity. No significant relationship between deletion size and clinical phenotype was observed among male patients, whereas in females the absence of NAIP was strongly associated with a severe phenotype (p less than 0.0001). SMA I was found in 75.6% of females and only 52.5% of males lacking NAIP. These results provided a possible molecular explanation for the sex-dependent phenotypic variation observed in SMA patients.
In inbred mouse strains, permissiveness to intracellular replication of Legionella pneumophila is controlled by a single locus (Lgn1), which maps to a region within distal chromosome 13 that contains multiple copies of the Birc1 gene. Genomic BAC clones from the critical interval were transferred into transgenic mice to complement functionally the Lgn1-associated susceptibility of A/J mice to L. pneumophila. Diez et al. (2003) found that 2 independent BAC clones that rescued susceptibility had an overlapping region of 56 kb in which the entire Lgn1 transcript must lie. The full-length transcript of Birc1e (also called Naip5) is coded in this region. The results indicated a role for Birc1e in macrophage resistance to L. pneumophila infection. BIRC1 proteins are members of the inhibitor of apoptosis protein (IAP) family, structurally defined by baculovirus inhibitor of apoptosis repeat (BIR) domains implicated in protein-protein interactions. An antiapoptotic effect of BIRC1 has been described. Induction of apoptosis seems to be important for pathogenesis of L. pneumophila in human macrophages in vitro.
Zamboni et al. (2006) noted that there are 14 amino acid differences in Birc1e between A/J and C57Bl/6 mice. A/J macrophages permit more L. pneumophila replication than C57Bl/6 macrophages. Zamboni et al. (2006) found that Birc1e-expressing cells from C57Bl/6 mice, but not those from A/J mice, responded to L. pneumophila infection and delivery of bacterial molecules to the cytosol with Casp1 (147678)-dependent cell death. Mutation analysis showed that the leucine-rich region of Birc1e regulated Birc1e activation, Casp1 activation, and Il1b (147720) secretion and required Ipaf (CARD12; 606831). Zamboni et al. (2006) concluded that Birc1e is a nucleotide-binding oligomerization-leucine-rich repeat protein involved in detection and control of intracellular L. pneumophila.
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Diez, E., Lee, S.-H., Gauthier, S., Yaraghi, Z., Tremblay, M., Vidal, S., Gros, P. Birc1e is the gene within the Lgn1 locus associated with resistance to Legionella pneumophila. Nature Genet. 33: 55-60, 2003. [PubMed: 12483212] [Full Text: https://doi.org/10.1038/ng1065]
Gotz, R., Karch, C., Digby, M. R., Troppmair, J., Rapp, U. R., Sendtner, M. The neuronal apoptosis inhibitory protein suppresses neuronal differentiation and apoptosis in PC12 cells. Hum. Molec. Genet. 9: 2479-2489, 2000. [PubMed: 11030753] [Full Text: https://doi.org/10.1093/hmg/9.17.2479]
Karki, R., Lee, E., Place, D., Samir, P., Mavuluri, J., Sharma, B. R., Balakrishnan, A., Malireddi, R. K. S., Geiger, R., Zhu, Q., Neale, G., Kanneganti, T.-D. IRF8 regulates transcription of Naips for NLRC4 inflammasome activation. Cell 173: 920-933, 2018. [PubMed: 29576451] [Full Text: https://doi.org/10.1016/j.cell.2018.02.055]
Kofoed, E. M., Vance, R. E. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477: 592-595, 2011. [PubMed: 21874021] [Full Text: https://doi.org/10.1038/nature10394]
Liston, P., Roy, N., Tamai, K., Lefebvre, C., Baird, S., Cherton-Horvat, G., Farahani, R., McLean, M., Ikeda, J.-E., MacKenzie, A., Korneluk, R. G. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 379: 349-353, 1996. [PubMed: 8552191] [Full Text: https://doi.org/10.1038/379349a0]
Novelli, G., Semprini, S., Capon, F., Dallapiccola, B. A possible role of NAIP gene deletions in sex-related spinal muscular atrophy phenotype variation. Neurogenetics 1: 29-30, 1997. [PubMed: 10735271] [Full Text: https://doi.org/10.1007/s100480050004]
Roy, N., Mahadevan, M. S., McLean, M., Shutler, G., Yaraghi, Z., Farahani, R., Baird, S., Besner-Johnston, A., Lefebvre, C., Kang, X., Salih, M., Aubry, H., Tamai, K., Guan, X., Ioannou, P., Crawford, T. O., de Jong, P. J., Surh, L., Ikeda, J.-E., Korneluk, R. G., MacKenzie, A. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 80: 167-178, 1995. [PubMed: 7813013] [Full Text: https://doi.org/10.1016/0092-8674(95)90461-1]
von Moltke, J., Trinidad, N. J., Moayeri, M., Kintzer, A. F., Wang, S. B., van Rooijen, N., Brown, C. R., Krantz, B. A., Leppla, S. H., Gronert, K., Vance, R. E. Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature 490: 107-111, 2012. [PubMed: 22902502] [Full Text: https://doi.org/10.1038/nature11351]
Zamboni, D. S., Kobayashi, K. S., Kohlsdorf, T., Ogura, Y., Long, E. M., Vance, R. E., Kuida, K., Mariathasan, S., Dixit, V. M., Flavell, R. A., Dietrich, W. F., Roy, C. R. The Birc1e cytosolic pattern-recognition receptor contributes to the detection and control of Legionella pneumophila infection. Nature Immun. 7: 318-325, 2006. [PubMed: 16444259] [Full Text: https://doi.org/10.1038/ni1305]
Zhao, Y., Yang, J., Shi, J., Gong, Y.-N., Lu, Q., Xu, H., Liu, L., Shao, F. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477: 596-600, 2011. [PubMed: 21918512] [Full Text: https://doi.org/10.1038/nature10510]