Alternative titles; symbols
HGNC Approved Gene Symbol: MUC5AC
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:1,157,953-1,201,138 (from NCBI)
Nguyen et al. (1990) pointed out that 3 classes of tracheobronchial mucin RNAs can be identified. Using probes representing each of the 3 groups, they concluded from somatic cell hybrid and in situ hybridization studies that one or more tracheobronchial mucin genes are localized on 11p15. They also found hybridization to chromosome 13 and concluded that this represented a tracheal mucin-related sequence. Because intestinal (MUC2; 158370) and tracheobronchial mucins appear to be different in their tissue distributions and cDNA nucleotide sequences, Nguyen et al. (1990) suggested that they may be coded by independent genes on 11p15, although it is possible that different mRNAs from the same primary transcript could be produced by differential splicing. From a human nasal polyp cDNA library, Meerzaman et al. (1994) isolated a 3.6-kb cDNA. The authenticity of the clone as MUC5 was established by mapping it to chromosome 11 through the study of human/rodent somatic cell hybrids. Meerzaman et al. (1994) found that it contained a 3,168 nucleotide open reading frame. Shankar et al. (1995) presented evidence that the gene transcripts for intestinal and tracheal mucin may be identical.
Reid and Harris (1998) used tissue in situ hybridization to study MUC5AC gene expression in midtrimester human fetal gut. Low levels of MUC5AC mRNA were detected in colonic epithelium at 13 weeks' gestation but not thereafter. In the stomach, abundant MUC5AC mRNA was detected at 23 weeks' gestation in the surface mucous cells of the epithelium but not in the neck mucous cells. This contrasted with MUC6 (158374) mRNA localization.
Using real-time RT-PCR, Moehle et al. (2006) found that MUC5AC was highly expressed in adult trachea and stomach. Expression was lower in adult lung and weak in fetal lung, and no expression was detected in other tissues.
By microarray analysis, Moehle et al. (2006) found coordinated downregulation of mucins, including MUC5AC, in ileum of Crohn disease and ulcerative colitis (see 266600) patients compared with controls. They identified an NF-kappa-B (NFKB; see 164011)-binding site in the MUC5AC promoter and showed that activation of the NF-kappa-B signaling pathway by inflammatory cytokine TNF-alpha (TNF; 191160) upregulated MUC5AC mRNA expression nearly 6-fold.
Sekine et al. (2006) found that expression of HATH1 (ATOH1; 601461) was lost in 5 of 8 gastric cancer (GC) cell lines examined, whereas normal gastric mucosa expressed HATH1. Expression of the gastric mucin genes MUC6 and MUC5AC showed a correlation with that of HATH1 in most GC cell lines. Overexpression of Math1, a mouse HATH1 homolog, in GC cells strongly enhanced MUC6 and MUC5AC mRNA levels. RNA interference-mediated downregulation of HATH1 in GC cells led to decreased expression of the mucin genes. Sekine et al. (2006) concluded that HATH1 is a transcriptional regulator for MUC5AC and MUC6 in GC cells and that HATH1 loss may be involved in gastric carcinogenesis.
Roy et al. (2014) showed that mouse Muc5b (600770), but not Muc5ac, is required for mucociliary clearance (MCC), for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL23A; 605580) production was reduced in Muc5b-null mice. By contrast, in mice that transgenically overexpressed Muc5b, macrophage functions improved. Mucous phenotypes in asthma (600807) and chronic obstructive pulmonary disease (COPD; 606963) were thought to be driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. Roy et al. (2014) concluded that by distinguishing a specific role for Muc5b in MCC and by determining its impact on bacterial infections and inflammation in mice, their results provided a refined framework for designing targeted therapies to control mucin secretion and restore MCC.
By stimulating normal human bronchial epithelial cells and human lung carcinoma cells with S100A8 (123885), S100A9 (123886), or S100A12 (603112), Kang et al. (2015) observed dose-dependent induction of MUC5AC expression. A TLR4 (603030) inhibitor largely blocked MUC5AC expression by all 3 S100 proteins, whereas neutralization of RAGE (AGER; 600214) inhibited only S100A12-mediated production of MUC5AC. S100 protein-mediated MUC5AC production was inhibited by pharmacologic agents that blocked signaling molecules involved in MUC5AC expression, such as MAP kinases (e.g., MAPK3; 601795), NFKB, and EGFR (131550). S100A8, S100A9, and S100A12 equally elicited phosphorylation of ERK and nuclear translocation of NFKB/degradation of cytosolic I-kappa-B (see 164008) through TLR4. S100A12, however, preferentially activated MAPK3 pathways rather than the NFKB pathway through RAGE. Kang et al. (2015) concluded that S100 proteins induce MUC5AC production in airway epithelial cells, suggesting that they serve as key mediators linking neutrophil-dominant airway inflammation to mucin hyperproduction.
Pigny et al. (1995) stated that they had evidence that the locus corresponding to 3 groups of partial tracheobronchial mucin cDNAs that was mapped to 11p15 and given the symbol MUC5 in fact comprises 2 distinct genes, which they provisionally called MUC5B and MUC5AC. Guyonnet Duperat et al. (1995) found physical mapping of 3 cDNAs, designated MUC5A, B, and C, using the strategy of analysis of CpG islands by pulsed field gel electrophoresis. The data suggested to the authors that MUC5A and MUC5C are part of the same gene, called MUC5AC, which is distinct form MUC5B. They also presented sequence data indicating that in the MUC5AC gene the tandem repeat domain is interrupted by a subdomain encoding a 130-amino acid cysteine-rich polypeptide. The consensus nucleotide sequence of this subdomain is also found in the MUC2 and MUC5B genes, which also map to 11p15.
Hasnain et al. (2011) noted that Muc5ac is detected in mice shortly before expulsion of Trichuris muris, which is used as a murine model of human T. trichiura worm infection, and that it is associated with production of Il13 (147683). They found that Muc5ac -/- mice were incapable of expelling T. muris from intestine and harbored a long-term chronic infection, despite developing strong Th2 responses. Muc5ac -/- mice had elevated Il13 levels and increased levels of the Th1 cytokine, Ifng (147570). Neutralization of Ifng resulted in an even stronger Th2 response, but the Muc5ac -/- mice remained highly susceptible to chronic T. muris infection. Exposure of T. muris to human cells producing MUC5AC, but not those producing MUC2, resulted in decreased worm viability. Lack of Muc5ac in mice also caused delayed expulsion of 2 other intestinal nematodes, Trichinella spiralis and Nippostrongylus brasiliensis. Hasnain et al. (2011) concluded that MUC5AC is a direct and critical mediator of resistance during intestinal nematode infection.
Guyonnet Duperat, V., Audie, J.-P., Debailleul, V., Laine, A., Buisine, M.-P., Galiegue-Zouitina, S., Pigny, P., Degand, P., Aubert, J.-P., Porchet, N. Characterization of the human mucin gene MUC5AC: a consensus cysteine-rich domain for 11p15 mucin genes? Biochem. J. 305: 211-219, 1995. [PubMed: 7826332] [Full Text: https://doi.org/10.1042/bj3050211]
Hasnain, S. Z., Evans, C. M., Roy, M., Gallagher, A. L., Kindrachuk, K. N., Barron, L., Dickey, B. F., Wilson, M. S., Wynn, T. A., Grencis, R. K., Thornton, D. J. Muc5ac: a critical component mediating the rejection of enteric nematodes. J. Exp. Med. 208: 893-900, 2011. [PubMed: 21502330] [Full Text: https://doi.org/10.1084/jem.20102057]
Kang, J. H., Hwang, S. M., Chung, I. Y. S100A8, S100A9 and S100A12 activate airway epithelial cells to produce MUC5AC via extracellular signal-regulated kinase and nuclear factor-kappa-B pathways. Immunology 144: 79-90, 2015. [PubMed: 24975020] [Full Text: https://doi.org/10.1111/imm.12352]
Meerzaman, D., Charles, P., Daskal, E., Polymeropoulos, M. H., Martin, B. M., Rose, M. C. Cloning and analysis of cDNA encoding a major airway glycoprotein, human tracheobronchial mucin (MUC5). J. Biol. Chem. 269: 12932-12939, 1994. [PubMed: 7513696]
Moehle, C., Ackermann, N., Langmann, T., Aslanidis, C., Kel, A., Kel-Margoulis, O., Schmitz-Madry, A., Zahn, A., Stremmel, W., Schmitz, G. Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease. J. Molec. Med. 84: 1055-1066, 2006. [PubMed: 17058067] [Full Text: https://doi.org/10.1007/s00109-006-0100-2]
Nguyen, V. C., Aubert, J. P., Gross, M. S., Porchet, N., Degand, P., Frezal, J. Assignment of human tracheobronchial mucin gene(s) to 11p15 and a tracheobronchial mucin-related sequence to chromosome 13. Hum. Genet. 86: 167-172, 1990. [PubMed: 2265829] [Full Text: https://doi.org/10.1007/BF00197699]
Pigny, P., Pratt, W. S., Laine, A., Leclercq, A., Swallow, D. M., Nguyen, V. C., Aubert, J. P., Porchet, N. The MUC5AC gene: RFLP analysis with the Jer58 probe. Hum. Genet. 96: 367-368, 1995. [PubMed: 7649560] [Full Text: https://doi.org/10.1007/BF00210427]
Reid, C. J., Harris, A. Developmental expression of mucin genes in the human gastrointestinal system. Gut 42: 220-226, 1998. [PubMed: 9536947] [Full Text: https://doi.org/10.1136/gut.42.2.220]
Roy, M. G., Livraghi-Butrico, A., Fletcher, A. A., McElwee, M. M., Evans, S. E., Boerner, R. M., Alexander, S. N., Bellinghausen, L. K., Song, A. S., Petrova, Y. M., Tuvim, M. J., Adachi, R., and 31 others. Muc5b is required for airway defence. Nature 505: 412-416, 2014. [PubMed: 24317696] [Full Text: https://doi.org/10.1038/nature12807]
Sekine, A., Akiyama, Y., Yanagihara, K., Yuasa, Y. Hath1 up-regulates gastric mucin gene expression in gastric cells. Biochem. Biophys. Res. Commun. 344: 1166-1171, 2006. [PubMed: 16647036] [Full Text: https://doi.org/10.1016/j.bbrc.2006.03.238]
Shankar, V., Gilmore, M. S., Sachdev, G. P. Further evidence that the human MUC2 gene transcripts in the intestine and trachea are identical. (Letter) Biochem. J. 306: 311-312, 1995. [PubMed: 7864825] [Full Text: https://doi.org/10.1042/bj3060311]