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|Coordinate||128,148,572 bp (GRCm38)|
|Base Change||C ⇒ A (forward strand)|
|Gene Name||integrin alpha X|
|Synonym(s)||Cd11c, CD11C (p150) alpha polypeptide|
|Chromosomal Location||128,129,547-128,150,656 bp (+)|
|MGI Phenotype||Mice homozygous for a targeted allele exhibit increased T cell proliferation, increased susceptibility to bacterial infection, and decreased susceptibility to EAE.|
|Amino Acid Change||Tyrosine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted sequence gene model|
AA Change: Y1053*
|Predicted Effect||probably null|
|Phenotypic Category||decrease in CD11b+ DCs in CD11c+ cells, decrease in CD11c+ DCs, decrease in pDCs in CD11c+ cells|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Semidominant|
|Last Updated||09/16/2016 2:36 PM by Katherine Timer|
|Record Created||10/15/2015 12:55 PM by Bruce Beutler|
The Adendritic phenotype was identified among G3 mice of the pedigree R3027, some of which showed reduced frequencies of CD11c+ conventional dendritic cells (cDCs) (Figure 1) and CD11b+ cDCs gated in CD11c+ cells (Figure 2) as well as an increased frequency of plasmacytoid DCs (pDCs) (Figure 3), all in the peripheral blood.
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 33 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Itgax: a C to A transversion at base pair 128,148,572 (v38) on chromosome 7, or base pair 19,044 in the GenBank genomic region NC_000073 encoding the Itgax gene. The strongest association was found with an additive model of linkage to the normalized frequency of CD11b+ cDCs gated in CD11c+ cells, wherein four variant homozygotes and 21 heterozygotes departed phenotypically from 19 homozygous reference mice with a P value of 9.542 x 10-12 (Figure 4). A substantial semidominant effect was observed in most of the assays.
The mutation corresponds to residue 3,211 in the mRNA sequence NM_021334 within exon 27 of 30 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of tyrosine 1053 (Y1053) to a premature stop codon (Y1053*) in the CD11c protein.
The Itgax gene encodes CD11c (alternatively, the integrin αX protein), which forms noncovalently linked dimers with CD18 (also called the integrin β2 protein; see the record for Joker) to form a functional integrin receptor, αXβ2. CD11c and CD18 are both type I transmembrane proteins. Similar to other α chains (i.e., CD11a and CD11b [see the record for invisible]), CD11c has a long extracellular domain, a transmembrane domain, and a short cytoplasmic domain (Figure 5).
CD11c and CD18 form the integrin head, with connections through upper and lower legs in each subunit to the cell membrane. Crystallographic analysis suggests that the extracellular domains of the integrins exist in a bent conformation in the latent, low-affinity state (Figure 6; PDB:4NEN, (1) and PDB:3K72, (2)). Destabilization of the interface between the α and β legs in the tailpiece results in shifting of the bent conformation and opening of the structure to an open high-affinity conformation where ligand may bind. On the cell surface, integrins equilibrate between the low- and high-affinity state; the equilibrium may be shifted by the presence of intracellular activators or extracellular ligands (3).
The extracellular domain of CD11c has several subdomains, including seven β-propeller repeats (designated as FG-GAP repeats) that form a β-propeller fold. A 200-amino acid (amino acids 152-330) von Willebrand factor A (VWFA) domain (alternatively, integrin I-domain) is the major CD11c ligand-binding site and separates the second and third FG-GAP repeat (4). The VWFA has six major α-helices and a β-sheet composed of five parallel and one anti-parallel β-strand. There is a large interface between the β-propeller domain of the α-subunit (containing the VWFA domain) and the VWFA-like domain of the β subunit (5). Evidence suggests that the VWFA domain regulates the conformation of the VWFA domain when it is in both subunits of the integrin (6). Ligand binding depends on the integrity of the metal ion-dependent adhesion site (MIDAS), a part of VWFA and VWFA-like domains, which binds to divalent cations and coordinates to a glutamine or aspartate residue in the ligand. A DXSXS sequence is a key metal-binding motif of the MIDAS. Please refer to reference (7) for an excellent review of integrin receptor extracellular domains and structure.
CD11c has several putative phosphorylation sites. Phosphorylation of Ser1158 in CD11c is essential for its adherence and phagocytosis functions (8). Mutation of Ser1158 to alanine (Ser1158Ala) resulted in reduced binding to iC3b. Mutation of Ser1158 did not result in changes in outside-in signaling, but does inhibit inside-out activation (see the Background section for more information about integrin signaling).
The Adendritic mutation results in substitution of tyrosine 1053 (Y1053) to a premature stop codon (Y1053*).
The CD11c/CD18 integrin is expressed on monocytes, macrophages, granulocytes, neutrophils, dendritic cells, lymphocytes, and natural killer cells. Expression of CD11c/CD18 increases upon cytokine or phorbol ester treatment as well as antigen-mediated activation. CD11c expression on mouse and human myeloid DCs after Toll-like receptor (TLR3/4/9) activation resulted in downregulation of CD11c expression (9).
Integrins are adhesion molecules that mediate cell-cell, cell-extracellular matrix, and cell-pathogen interactions. They regulate cell migration and morphogenesis by coordinating regulatory signals from inside and outside the cell, with the physical machinery for cell movement. Most integrins, including β2-integrins, link to and regulate the actin cytoskeleton. Their ligands are diverse, but most possess a short peptide motif containing an acidic residue (aspartate or glutamate) positioned in a flexible loop. There are 24 distinct integrins formed by a combination of α and β subunits, and those containing the β2 subunit are leukocyte-specific [reviewed in (10)]. Each leukocyte class expresses a distinct pattern of integrins that changes in functional state, density and localization in response to intra- and extracellular cues, including protein modifications (e.g. phosphorylation), cytokines, chemokines, and other cell adhesion molecules. However, all leukocytes express one or more β2-containing integrin. The β2-containing integrins are αLβ2 (CD11a/CD18; also called leukocyte function-associated antigen 1, LFA-1), αMβ2 (CD11b/CD18; also called MAC-1), αXβ2 (CD11c/CD18; also called p150,95 or CR4) and αDβ2 (CD11d/CD18). The CD11/CD18 integrins are referenced collectively as the “leukocyte” integrins, and mediate leukocyte adhesion during inflammatory responses to infections and also during wound repair.
Leukocytes circulate in the blood in a quiescent state of low adhesiveness, becoming activated and migrating into tissues during microbial invasion in order to defend against infection. The β2-containing integrins are thus inactive when leukocytes are in a resting state, and must be rapidly activated during infection to mediate leukocyte adhesion to various cell types such as endothelial cells of vessel walls and antigen-presenting cells. Integrins transmit signals bidirectionally across the plasma membrane. “Outside-in” signaling occurs when ligands bind to integrins, and serves to mediate adhesion and to initiate downstream signaling. Ligand binding induces the clustering of integrins on the cell surface and enables the recruitment of signaling molecules to the cytoplasmic face of the receptor.
“Inside-out” signaling primes integrins for ligand binding (Figure 7). The adhesive state of integrins may be modulated by conformational changes in the integrin itself, or possibly by clustering of integrins on the cell surface to increase avidity (7)). The intracellular domain of the β2 chain has been shown to influence integrin adhesive activity in the case of LFA-1 (11;12). How this process is regulated is largely unknown, but Rho family GTPases and the cytoskeletal protein talin have been shown to play a role. Knockdown of the leukocyte-specific inhibitory RhoH in peripheral blood lymphocytes results in a constitutively adherent phenotype towards ICAM-1, demonstrating that RhoH promotes the nonadhesive state of LFA-1 (integrin αLβ2) (13). Conversely, knockdown of talin impairs TCR-induced adhesion to ICAM-1 (14). Another Rho GTPase, RhoA, promotes neutrophil adhesion through β2 integrin (15).
CD11c has proposed functions in phagocytosis, cell migration, cytokine production by monocytes/macrophages, and induction of T cell proliferation by Langerhans cells.
CD11c/CD18 has several functions, including monocyte and neutrophil binding to and transmigration through the endothelium (16), conjugate formation between cytotoxic T cells and target cells (16-19), phagocytic clearance of bacteria and apoptotic cells (19-21). The ligands that mediate these functions are summarized in Table 1.
Table 1. CD11c/CD18 ligands
In a mouse model with inducible ablation of Itgax (CD11c-DTR), exposure to diphtheria toxin resulted in loss of CD11c+ cells (35;36). Constitutive deletion of CD11c resulted in loss of CD11c+ DCs. Itgax-deficient mice immunized with EAE exhibited increased T cell proliferation, increased IL-12 secretion, increased IL-2 secretion, reduced interferon-gamma secretion, decreased IL-17 secretion, and reduced TNF secretion compared to wild-type littermates (37). Furthermore, the Itgax-deficient mice exhibited increased susceptibility to pneumococcal infection compared to controls (38).
The loss of CD11c DCs in the Adendritic mouse indicates that the CD11cAdendritic protein exhibits loss of function. Expression of the CD11cAdendritic protein has not been examined.
Adendritic(F):5'- TCTGCACCAGCTCTATCGAG -3'
Adendritic(R):5'- AATGTGATTTCAGCCTCACTCAG -3'
Adendritic_seq(F):5'- AGCTCTATCGAGGCCTGCATG -3'
Adendritic_seq(R):5'- GGAGCAACACCTTTTTCTGCAATG -3'
1. Sen, M., Yuki, K., and Springer, T. A. (2013) An Internal Ligand-Bound, Metastable State of a Leukocyte Integrin, alphaXbeta2. J Cell Biol. 203, 629-642.
2. Xie, C., Zhu, J., Chen, X., Mi, L., Nishida, N., and Springer, T. A. (2010) Structure of an Integrin with an alphaI Domain, Complement Receptor Type 4. EMBO J. 29, 666-679.
3. Takagi, J., Petre, B. M., Walz, T., and Springer, T. A. (2002) Global Conformational Rearrangements in Integrin Extracellular Domains in Outside-in and Inside-Out Signaling. Cell. 110, 599-11.
4. Springer, T. A. (1997) Folding of the N-Terminal, Ligand-Binding Region of Integrin Alpha-Subunits into a Beta-Propeller Domain. Proc Natl Acad Sci U S A. 94, 65-72.
5. Xiong, J. P., Stehle, T., Diefenbach, B., Zhang, R., Dunker, R., Scott, D. L., Joachimiak, A., Goodman, S. L., and Arnaout, M. A. (2001) Crystal Structure of the Extracellular Segment of Integrin Alpha Vbeta3. Science. 294, 339-345.
6. Lu, C., Shimaoka, M., Zang, Q., Takagi, J., and Springer, T. A. (2001) Locking in Alternate Conformations of the Integrin alphaLbeta2 I Domain with Disulfide Bonds Reveals Functional Relationships among Integrin Domains. Proc Natl Acad Sci U S A. 98, 2393-2398.
7. Shimaoka, M., Takagi, J., and Springer, T. A. (2002) Conformational Regulation of Integrin Structure and Function. Annu Rev Biophys Biomol Struct. 31, 485-516.
8. Uotila, L. M., Aatonen, M., and Gahmberg, C. G. (2013) Integrin CD11c/CD18 Alpha-Chain Phosphorylation is Functionally Important. J Biol Chem. 288, 33494-33499.
9. Singh-Jasuja, H., Thiolat, A., Ribon, M., Boissier, M. C., Bessis, N., Rammensee, H. G., and Decker, P. (2013) The Mouse Dendritic Cell Marker CD11c is Down-Regulated upon Cell Activation through Toll-Like Receptor Triggering. Immunobiology. 218, 28-39.
10. Harris, E. S., McIntyre, T. M., Prescott, S. M., and Zimmerman, G. A. (2000) The Leukocyte Integrins. J Biol Chem. 275, 23409-23412.
11. Hibbs, M. L., Jakes, S., Stacker, S. A., Wallace, R. W., and Springer, T. A. (1991) The Cytoplasmic Domain of the Integrin Lymphocyte Function-Associated Antigen 1 Beta Subunit: Sites Required for Binding to Intercellular Adhesion Molecule 1 and the Phorbol Ester-Stimulated Phosphorylation Site. J Exp Med. 174, 1227-1238.
12. Peter, K., and O'Toole, T. E. (1995) Modulation of Cell Adhesion by Changes in Alpha L Beta 2 (LFA-1, CD11a/CD18) Cytoplasmic domain/cytoskeleton Interaction. J Exp Med. 181, 315-326.
13. Cherry, L. K., Li, X., Schwab, P., Lim, B., and Klickstein, L. B. (2004) RhoH is Required to Maintain the Integrin LFA-1 in a Nonadhesive State on Lymphocytes. Nat Immunol. 5, 961-967.
14. Simonson, W. T., Franco, S. J., and Huttenlocher, A. (2006) Talin1 Regulates TCR-Mediated LFA-1 Function. J Immunol. 177, 7707-7714.
15. Laudanna, C., Campbell, J. J., and Butcher, E. C. (1996) Role of Rho in Chemoattractant-Activated Leukocyte Adhesion through Integrins. Science. 271, 981-983.
16. Keizer, G. D., Borst, J., Visser, W., Schwarting, R., de Vries, J. E., and Figdor, C. G. (1987) Membrane Glycoprotein p150,95 of Human Cytotoxic T Cell Clone is Involved in Conjugate Formation with Target Cells. J Immunol. 138, 3130-3136.
17. te Velde, A. A., Keizer, G. D., and Figdor, C. G. (1987) Differential Function of LFA-1 Family Molecules (CD11 and CD18) in Adhesion of Human Monocytes to Melanoma and Endothelial Cells. Immunology. 61, 261-267.
18. Stacker, S. A., and Springer, T. A. (1991) Leukocyte Integrin P150,95 (CD11c/CD18) Functions as an Adhesion Molecule Binding to a Counter-Receptor on Stimulated Endothelium. J Immunol. 146, 648-655.
19. Keizer, G. D., Te Velde, A. A., Schwarting, R., Figdor, C. G., and De Vries, J. E. (1987) Role of p150,95 in Adhesion, Migration, Chemotaxis and Phagocytosis of Human Monocytes. Eur J Immunol. 17, 1317-1322.
20. Schlesinger, L. S., Bellinger-Kawahara, C. G., Payne, N. R., and Horwitz, M. A. (1990) Phagocytosis of Mycobacterium Tuberculosis is Mediated by Human Monocyte Complement Receptors and Complement Component C3. J Immunol. 144, 2771-2780.
21. Mevorach, D., Mascarenhas, J. O., Gershov, D., and Elkon, K. B. (1998) Complement-Dependent Clearance of Apoptotic Cells by Human Macrophages. J Exp Med. 188, 2313-2320.
22. Frick, C., Odermatt, A., Zen, K., Mandell, K. J., Edens, H., Portmann, R., Mazzucchelli, L., Jaye, D. L., and Parkos, C. A. (2005) Interaction of ICAM-1 with Beta 2-Integrin CD11c/CD18: Characterization of a Peptide Ligand that Mimics a Putative Binding Site on Domain D4 of ICAM-1. Eur J Immunol. 35, 3610-3621.
23. Blackford, J., Reid, H. W., Pappin, D. J., Bowers, F. S., and Wilkinson, J. M. (1996) A Monoclonal Antibody, 3/22, to Rabbit CD11c which Induces Homotypic T Cell Aggregation: Evidence that ICAM-1 is a Ligand for CD11c/CD18. Eur J Immunol. 26, 525-531.
24. Ihanus, E., Uotila, L. M., Toivanen, A., Varis, M., and Gahmberg, C. G. (2007) Red-Cell ICAM-4 is a Ligand for the monocyte/macrophage Integrin CD11c/CD18: Characterization of the Binding Sites on ICAM-4. Blood. 109, 802-810.
25. Sadhu, C., Ting, H. J., Lipsky, B., Hensley, K., Garcia-Martinez, L. F., Simon, S. I., and Staunton, D. E. (2007) CD11c/CD18: Novel Ligands and a Role in Delayed-Type Hypersensitivity. J Leukoc Biol. 81, 1395-1403.
26. Gower, R. M., Wu, H., Foster, G. A., Devaraj, S., Jialal, I., Ballantyne, C. M., Knowlton, A. A., and Simon, S. I. (2011) CD11c/CD18 Expression is Upregulated on Blood Monocytes during Hypertriglyceridemia and Enhances Adhesion to Vascular Cell Adhesion Molecule-1. Arterioscler Thromb Vasc Biol. 31, 160-166.
27. Bilsland, C. A., Diamond, M. S., and Springer, T. A. (1994) The Leukocyte Integrin p150,95 (CD11c/CD18) as a Receptor for iC3b. Activation by a Heterologous Beta Subunit and Localization of a Ligand Recognition Site to the I Domain. J Immunol. 152, 4582-4589.
28. Nham, S. U. (1999) Characteristics of Fibrinogen Binding to the Domain of CD11c, an Alpha Subunit of p150,95. Biochem Biophys Res Commun. 264, 630-634.
29. Postigo, A. A., Corbi, A. L., Sanchez-Madrid, F., and de Landazuri, M. O. (1991) Regulated Expression and Function of CD11c/CD18 Integrin on Human B Lymphocytes. Relation between Attachment to Fibrinogen and Triggering of Proliferation through CD11c/CD18. J Exp Med. 174, 1313-1322.
30. Loike, J. D., Sodeik, B., Cao, L., Leucona, S., Weitz, J. I., Detmers, P. A., Wright, S. D., and Silverstein, S. C. (1991) CD11c/CD18 on Neutrophils Recognizes a Domain at the N Terminus of the A Alpha Chain of Fibrinogen. Proc Natl Acad Sci U S A. 88, 1044-1048.
31. Garnotel, R., Rittie, L., Poitevin, S., Monboisse, J. C., Nguyen, P., Potron, G., Maquart, F. X., Randoux, A., and Gillery, P. (2000) Human Blood Monocytes Interact with Type I Collagen through Alpha x Beta 2 Integrin (CD11c-CD18, gp150-95). J Immunol. 164, 5928-5934.
32. Diamond, M. S., Alon, R., Parkos, C. A., Quinn, M. T., and Springer, T. A. (1995) Heparin is an Adhesive Ligand for the Leukocyte Integrin Mac-1 (CD11b/CD1). J Cell Biol. 130, 1473-1482.
33. Vorup-Jensen, T., Chi, L., Gjelstrup, L. C., Jensen, U. B., Jewett, C. A., Xie, C., Shimaoka, M., Linhardt, R. J., and Springer, T. A. (2007) Binding between the Integrin alphaXbeta2 (CD11c/CD18) and Heparin. J Biol Chem. 282, 30869-30877.
34. Ingalls, R. R., and Golenbock, D. T. (1995) CD11c/CD18, a Transmembrane Signaling Receptor for Lipopolysaccharide. J Exp Med. 181, 1473-1479.
35. Ohnmacht, C., Pullner, A., King, S. B., Drexler, I., Meier, S., Brocker, T., and Voehringer, D. (2009) Constitutive Ablation of Dendritic Cells Breaks Self-Tolerance of CD4 T Cells and Results in Spontaneous Fatal Autoimmunity. J Exp Med. 206, 549-559.
36. Bar-On, L., and Jung, S. (2010) Defining in Vivo Dendritic Cell Functions using CD11c-DTR Transgenic Mice. Methods Mol Biol. 595, 429-442.
37. Bullard, D. C., Hu, X., Adams, J. E., Schoeb, T. R., and Barnum, S. R. (2007) P150/95 (CD11c/CD18) Expression is Required for the Development of Experimental Autoimmune Encephalomyelitis. Am J Pathol. 170, 2001-2008.
38. Ren, B., McCrory, M. A., Pass, C., Bullard, D. C., Ballantyne, C. M., Xu, Y., Briles, D. E., and Szalai, A. J. (2004) The Virulence Function of Streptococcus Pneumoniae Surface Protein A Involves Inhibition of Complement Activation and Impairment of Complement Receptor-Mediated Protection. J Immunol. 173, 7506-7512.
|Science Writers||Anne Murray|
|Illustrators||Peter Jurek, Katherine Timer|
|Authors||Ming Zeng, Xue Zhong, Bruce Beutler|
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