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|Coordinate||20,290,383 bp (GRCm38)|
|Base Change||G ⇒ T (forward strand)|
|Gene Name||engulfment and cell motility 1|
|Synonym(s)||C230095H21Rik, 6330578D22Rik, CED-12|
|Chromosomal Location||20,090,596-20,608,353 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the engulfment and cell motility protein family. These proteins interact with dedicator of cytokinesis proteins to promote phagocytosis and cell migration. Increased expression of this gene and dedicator of cytokinesis 1 may promote glioma cell invasion, and single nucleotide polymorphisms in this gene may be associated with diabetic nephropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]
PHENOTYPE: Mice homozygous for a knock-out allele exhibit impaired Sertoli cell phagocytosis of apoptotic male germ cells. [provided by MGI curators]
|Amino Acid Change||Glutamic Acid changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000072334] [ENSMUSP00000152595]|
AA Change: E326*
|Predicted Effect||probably null|
|Predicted Effect||probably null|
|Predicted Effect||probably null|
|Alleles Listed at MGI|
|Mode of Inheritance||Unknown|
|Last Updated||2019-01-05 8:26 AM by Diantha La Vine|
|Record Created||2018-02-16 12:46 PM by Anne Murray|
The Edinburg phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R5947, some of which showed reduced CD4 to CD8 T cell ratios (Figure 1) as well as reduced frequencies of B cells (Figure 2) and CD4+ T cells in CD3+ T cells (Figure 3) with concomitant increased frequencies of B1 cells (Figure 4), CD8+ T cells (Figure 5), and CD8+ T cells in CD3+ T cells (Figure 6), all in the peripheral blood. The expression of B220 on peripheral blood B cells was also reduced (Figure 7).
|Nature of Mutation|
Whole exome HiSeq sequencing of the R4425 grandsire identified 63 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Elmo1: a G to T transversion at base pair 20,290,383 (v38) on chromosome 13, or base pair 199,877 in the GenBank genomic region NC_000079. The strongest association was found with a recessive model of inheritance to the B220 expression on B cells phenotype, wherein seven variant homozygotes departed phenotypically from 12 homozygous reference mice and 21 heterozygous mice with a P value of 7.22 x 10-9 (Figure 8). A substantial semidominant effect was observed in most of the assays but the mutation is preponderantly recessive, and in no assay was a purely dominant effect observed.
The mutation corresponds to residue 1,314 in the mRNA sequence NM_080288 within exon 13 of 22 total exons.
The mutated nucleotide is indicated in red. The mutation results in substitution of glutamic acid 326 for a premature stop codon (E326*) in the ELMO1 protein.
ELMO1 (engulfment and cell motility protein 1; alternatively, CED-12) has an ELMO domain (amino acids 391 to 492), a pleckstrin homology (PH) domain (amino acids 555 to 676), and a Pro-rich SH3-binding motif (amino acids 707 to 714) (Figure 9). Amino acids 536 to 557 and amino acids 679 to 697 are predicted to be α-helical regions. Amino acids 1 to 280 do not comprise a specific domain, but bind to RhoG (1), ezrin/radixin/moesin (ERM) proteins (2), and Salmonella IpgB1 (3).
The function of the ELMO domain is unknown. PH domains bind proteins such as the beta/gamma subunits of heterotrimeric G proteins and protein kinase C as well as phosphatidylinositol within biological membranes. PH domains recruit proteins to different membranes, thus targeting them to appropriate cellular compartments or enabling them to interact with other components of the signal transduction pathways. The ELMO domain, PH domain, SH3-binding motif, and the α-helical extension of the PH domain all mediate interaction between ELMO1 and DOCK180 (4-6). The interaction of ELMO1 with the DOCK180/Rac1 complex in trans stabilizes Rac1 in a nucleotide-free transition state (7).
ELMO1 is phosphorylated at several tyrosine residues. Src phosphorylates ELMO1 on tyrosine 724 (8). Src-mediated ELMO1 phosphorylation promotes cell spreading through Rac1 activation. Tyr18, Tyr216, Tyr511, Tyr395, and Tyr720 are phosphorylated by the Src family kinase Hck (9). Hck-mediated phosphorylation of ELMO1 promotes Rac1 activation.
The Edinburg mutation results in substitution of glutamic acid 326 for a premature stop codon (E326*) in the ELMO1 protein; residue 326 is within the ELMO domain.
ELMO1 is ubiquitously expressed and localizes to the cytoplasm (NCBI).
ELMO1 is an adaptor protein that interacts with members of the DOCK family (see the records frazz, moonlight, and snowdrop for information about DOCK2, DOCK7, and DOCK8, respectively) to promote the activation of the small GTPase RAC, phagocytosis, and cell migration (Figure 10) (10-13).
ELMO1 functions downstream of the phagocytic receptor BAI1 (see the record for bunting) during apoptotic cell clearance (14;15). BAI1 functions in the recognition and subsequent internalization of apoptotic cells (15). In macrophages, BAI1 functions as a pattern recognition receptor in the phagocytic uptake of Gram-negative bacteria (15). BAI1 interacts with ELMO1, which subsequently activates DOCK180 (16). ELMO proteins engage DOCK180 in at least three different ways: (i) an ELMO proline-rich motif interacts with the DOCK180 SH3 domain (ii) the ELMO PH domain interacts with the nucleotide free Rac–DOCK complex; and (iii) elements within the last 100 residues of ELMO (distinct from the proline-rich motif) interact with elements within the first 357 residues of DOCK180 (distinct from the SH3 domain) (5;10;17). Interaction of ELMO with the SH3 domain relieves a steric inhibition within DOCK180 in which the SH3 domain interacts with the DOCK180 DHR-2 (DOCK homology region 2) domain to block Rac binding (17). ELMO1 also inhibits the ubiquitination of DOCK180, subsequently resulting in increased levels of DOCK180 (18).
ELMO1 is essential for DOCK2-dependent lymphocyte migration (19;20). In human T cells, the human immunodeficiency virus (HIV) Nef protein binds to the DOCK2-ELMO1 complex and inhibits T cell chemotaxis by promoting generalized instead of polarized Rac activation (21). CD4+ T cells from Elmo1-deficient (Elmo1-/-) mice exhibited impaired polarization, Rac activation, and chemotaxis in response to CCR7 and CXCR4 stimulation (19;20). After undergoing a selection process in primary lymphoid organs such as bone marrow and thymus, naive lymphocytes continually home from blood to secondary lymphoid organs (SLO), such as peripheral and mesenteric lymph nodes (PLN and MLN, respectively), spleen and gut-associated lymphoid tissue including Peyer's patches (PP). Inside SLO, T and B cells localize in T cell area and B cell follicles, respectively, where they screen antigen (Ag)-presenting cells for specific surface Ag complexes. Upon activation with cognate Ag in presence of costimulatory molecules, T and B cells undergo specific changes in microenvironmental positioning. These changes allow T–B cell interactions at the T cell area–B cell follicle border and in germinal center (GC) light zones to occur. Activated T and B cells eventually leave SLO to accumulate at sites of inflammation or other effector sites. Lymphocyte migration is regulated by chemokines, integrins and adhesion receptors. DOCK2 mediates CCR7- and CXCR4-dependent Rac activation and chemotaxis.
ELMO1 functions in G-protein coupled receptor (GPCR)-mediated chemotaxis upon stimulation of CXCR4 (22). Activation of chemokine receptors [see the record for lanzhou for information about CCR7] promotes an interaction between ELMO1 and Gβγ, which causes translocation of ELMO1 to the membrane. ELMO1/DOCK180 subsequently activates Rac1.
ELMO1 mediates bacteria internalization and intestinal inflammation as well as autophagy induction and bacterial clearance during enteric infection (23;24). Elmo1-deficient macrophages showed reduced release of pro-inflammatory cytokines, reduced Rac1 activation, and impaired activation of NF-κB (see the record for Finlay), ERK1/2 (see the record for wabasha), and p38 MAP kinases (see the record for Wanzhou) after Salmonella infection (23). After Salmonella infection, ELMO1 regulates the acidification of phagolysosomes as well as the enzymatic activity of lysosomal enzymes (24).
ELMO1 interacts with the ERM (ezrin/radixin/moesin) proteins (2), which function in cell migration, cell adhesion, cell shape maintenance, and microvilli formation by cross-linking the plasma membrane with the actin cytoskeleton. ERM proteins are important players in signaling pathways regulated by Rho-family GTPases. These pathways control cell morphogenesis, adhesion, motility and proliferation in response to a variety of cellular stimuli. ERM proteins regulate B cell membrane raft dynamics and BCR clustering (25). ERM proteins are involved in cell cortex organization at two important stages of T lymphocyte physiology: during the polarization and migration in response to chemokines, and during the formation of the immunological synapse upon antigen recognition. During the formation of the immunological, the ERM proteins function in cell polarity during lymphocyte migration and in T cell-APC interactions. The ERM proteins also are critical for cell polarization during T lymphocyte migration. ERM proteins are involved in the generation of the migrating T cell uropod and in the anchoring of various transmembrane proteins (e.g., ICAMs, CD43, CD44 [see the record for Jialin], PSGL-1 and the death receptor CD95/Fas [see the record for cherry]) to the uropod.
The Mediator complex bridges the general transcription machinery with gene-specific regulatory proteins. ELMO1 interacts with the Mediator complex subunit Med31 and promotes the cytoplasmic localization of Med31 as well as Med31 ubiquitination (26). During Salmonella infection, ELMO1 and Med31 affect the expression of Il10 and Il33.
ELMO1 protects renal structure and ultrafiltration by reducing apoptosis during kidney development in the zebrafish (27). During the pathogenesis of chronic renal injury, ELMO1 dysregulates extracellular matrix (ECM) metabolism as well as reduces the cell adhesive properties of ECMs (28). Mutations in ELMO1 are associated with susceptibility to diabetic nephropathy (29-31). In type 1 diabetic Ins2Akita mice, reduced levels of ELMO1 alleviated albuminuria and caused changes to the glomerular histology, while increased levels of ELMO1 resulted in increased levels of oxidative stress markers and increased expression of fibrogenic genes (29).
Elmo1-deficient (Elmo1-/-; Elmo1tm1.2Ravi/tm1.2Ravi) mice are overtly normal (14). Elmo1-/- mice exhibited disrupted seminiferous epithelium, multinucleated giant cells, uncleared apoptotic germ cells, and decreased sperm output (14). A second Elmo1-/- mouse model (Elmo1tm1a(EUCOMM)Wtsi/tm1a(EUCOMM)Wtsi) exhibited reduced numbers of mature B cells, natural killer T cells, and CD4+ CD25+ regulatory T cells with concomitant increased numbers of effector memory CD4+ T cells. Some mice also exhibited decreased fasted circulating glucose levels.
The immune phenotypes observed in the Edinburg mice indicate loss of ELMO1Edinburg function. The Edinburg mutation may alter the ability of ELMO1Edinburg to interact with the ERM proteins, namely during formation of the immunologial synapse after antigen recognition. Also, the interaction between ELMO1Edinburg and DOCK2 may be affected.
Edinburg(F):5'- GAGAGAGGCCTGAGTTCTAAC -3'
Edinburg(R):5'- TTCTGCAAAGCACAAGAGGAC -3'
Edinburg_seq(F):5'- GTTCTAACTCAGGACACGACTTG -3'
Edinburg_seq(R):5'- ACACGTTCGATGCGACTGAG -3'
1. Katoh, H., and Negishi, M. (2003) RhoG Activates Rac1 by Direct Interaction with the Dock180-Binding Protein Elmo. Nature. 424, 461-464.
2. Grimsley, C. M., Lu, M., Haney, L. B., Kinchen, J. M., and Ravichandran, K. S. (2006) Characterization of a Novel Interaction between ELMO1 and ERM Proteins. J Biol Chem. 281, 5928-5937.
3. Handa, Y., Suzuki, M., Ohya, K., Iwai, H., Ishijima, N., Koleske, A. J., Fukui, Y., and Sasakawa, C. (2007) Shigella IpgB1 Promotes Bacterial Entry through the ELMO-Dock180 Machinery. Nat Cell Biol. 9, 121-128.
4. Komander, D., Patel, M., Laurin, M., Fradet, N., Pelletier, A., Barford, D., and Cote, J. F. (2008) An Alpha-Helical Extension of the ELMO1 Pleckstrin Homology Domain Mediates Direct Interaction to DOCK180 and is Critical in Rac Signaling. Mol Biol Cell. 19, 4837-4851.
5. Lu, M., Kinchen, J. M., Rossman, K. L., Grimsley, C., deBakker, C., Brugnera, E., Tosello-Trampont, A. C., Haney, L. B., Klingele, D., Sondek, J., Hengartner, M. O., and Ravichandran, K. S. (2004) PH Domain of ELMO Functions in Trans to Regulate Rac Activation Via Dock180. Nat Struct Mol Biol. 11, 756-762.
6. Sevajol, M., Reiser, J. B., Chouquet, A., Perard, J., Ayala, I., Gans, P., Kleman, J. P., and Housset, D. (2012) The C-Terminal Polyproline-Containing Region of ELMO Contributes to an Increase in the Life-Time of the ELMO-DOCK Complex. Biochimie. 94, 823-828.
7. Lu, M., Kinchen, J. M., Rossman, K. L., Grimsley, C., deBakker, C., Brugnera, E., Tosello-Trampont, A. C., Haney, L. B., Klingele, D., Sondek, J., Hengartner, M. O., and Ravichandran, K. S. (2004) PH Domain of ELMO Functions in Trans to Regulate Rac Activation Via Dock180. Nat Struct Mol Biol. 11, 756-762.
8. Makino, Y., Tsuda, M., Ohba, Y., Nishihara, H., Sawa, H., Nagashima, K., and Tanaka, S. (2015) Tyr724 Phosphorylation of ELMO1 by Src is Involved in Cell Spreading and Migration Via Rac1 Activation. Cell Commun Signal. 13, 35-015-0113-y.
9. Yokoyama, N., deBakker, C. D., Zappacosta, F., Huddleston, M. J., Annan, R. S., Ravichandran, K. S., and Miller, W. T. (2005) Identification of Tyrosine Residues on ELMO1 that are Phosphorylated by the Src-Family Kinase Hck. Biochemistry. 44, 8841-8849.
10. Sanui, T., Inayoshi, A., Noda, M., Iwata, E., Oike, M., Sasazuki, T., and Fukui, Y. (2003) DOCK2 is Essential for Antigen-Induced Translocation of TCR and Lipid Rafts, but Not PKC-Theta and LFA-1, in T Cells. Immunity. 19, 119-129.
11. Grimsley, C. M., Kinchen, J. M., Tosello-Trampont, A. C., Brugnera, E., Haney, L. B., Lu, M., Chen, Q., Klingele, D., Hengartner, M. O., and Ravichandran, K. S. (2004) Dock180 and ELMO1 Proteins Cooperate to Promote Evolutionarily Conserved Rac-Dependent Cell Migration. J Biol Chem. 279, 6087-6097.
12. Hiramoto, K., Negishi, M., and Katoh, H. (2006) Dock4 is Regulated by RhoG and Promotes Rac-Dependent Cell Migration. Exp Cell Res. 312, 4205-4216.
13. Komander, D., Patel, M., Laurin, M., Fradet, N., Pelletier, A., Barford, D., and Cote, J. F. (2008) An Alpha-Helical Extension of the ELMO1 Pleckstrin Homology Domain Mediates Direct Interaction to DOCK180 and is Critical in Rac Signaling. Mol Biol Cell. 19, 4837-4851.
14. Elliott, M. R., Zheng, S., Park, D., Woodson, R. I., Reardon, M. A., Juncadella, I. J., Kinchen, J. M., Zhang, J., Lysiak, J. J., and Ravichandran, K. S. (2010) Unexpected Requirement for ELMO1 in Clearance of Apoptotic Germ Cells in Vivo. Nature. 467, 333-337.
15. Park, D., Tosello-Trampont, A. C., Elliott, M. R., Lu, M., Haney, L. B., Ma, Z., Klibanov, A. L., Mandell, J. W., and Ravichandran, K. S. (2007) BAI1 is an Engulfment Receptor for Apoptotic Cells Upstream of the ELMO/Dock180/Rac Module. Nature. 450, 430-434.
16. Lu, M., and Ravichandran, K. S. (2006) Dock180-ELMO Cooperation in Rac Activation. Methods Enzymol. 406, 388-402.
17. Lu, M., Kinchen, J. M., Rossman, K. L., Grimsley, C., Hall, M., Sondek, J., Hengartner, M. O., Yajnik, V., and Ravichandran, K. S. (2005) A Steric-Inhibition Model for Regulation of Nucleotide Exchange Via the Dock180 Family of GEFs. Curr Biol. 15, 371-377.
18. Makino, Y., Tsuda, M., Ichihara, S., Watanabe, T., Sakai, M., Sawa, H., Nagashima, K., Hatakeyama, S., and Tanaka, S. (2006) Elmo1 Inhibits Ubiquitylation of Dock180. J Cell Sci. 119, 923-932.
19. Stevenson, C., de la Rosa, G., Anderson, C. S., Murphy, P. S., Capece, T., Kim, M., and Elliott, M. R. (2014) Essential Role of Elmo1 in Dock2-Dependent Lymphocyte Migration. J Immunol. 192, 6062-6070.
20. Sanui, T., Inayoshi, A., Noda, M., Iwata, E., Stein, J. V., Sasazuki, T., and Fukui, Y. (2003) DOCK2 Regulates Rac Activation and Cytoskeletal Reorganization through Interaction with ELMO1. Blood. 102, 2948-2950.
21. Janardhan, A., Swigut, T., Hill, B., Myers, M. P., and Skowronski, J. (2004) HIV-1 Nef Binds the DOCK2-ELMO1 Complex to Activate Rac and Inhibit Lymphocyte Chemotaxis. PLoS Biol. 2, E6.
22. Wang, Y., Xu, X., Pan, M., and Jin, T. (2016) ELMO1 Directly Interacts with Gbetagamma Subunit to Transduce GPCR Signaling to Rac1 Activation in Chemotaxis. J Cancer. 7, 973-983.
23. Das, S., Sarkar, A., Choudhury, S. S., Owen, K. A., Castillo, V., Fox, S., Eckmann, L., Elliott, M. R., Casanova, J. E., and Ernst, P. B. (2015) ELMO1 has an Essential Role in the Internalization of Salmonella Typhimurium into Enteric Macrophages that Impacts Disease Outcome. Cell Mol Gastroenterol Hepatol. 1, 311-324.
24. Sarkar, A., Tindle, C., Pranadinata, R. F., Reed, S., Eckmann, L., Stappenbeck, T. S., Ernst, P. B., and Das, S. (2017) ELMO1 Regulates Autophagy Induction and Bacterial Clearance during Enteric Infection. J Infect Dis. 216, 1655-1666.
25. Pore, D., and Gupta, N. (2015) The Ezrin-Radixin-Moesin Family of Proteins in the Regulation of B-Cell Immune Response. Crit Rev Immunol. 35, 15-31.
26. Mauldin, J. P., Lu, M., Das, S., Park, D., Ernst, P. B., and Ravichandran, K. S. (2013) A Link between the Cytoplasmic Engulfment Protein Elmo1 and the Mediator Complex Subunit Med31. Curr Biol. 23, 162-167.
27. Sharma, K. R., Heckler, K., Stoll, S. J., Hillebrands, J. L., Kynast, K., Herpel, E., Porubsky, S., Elger, M., Hadaschik, B., Bieback, K., Hammes, H. P., Nawroth, P. P., and Kroll, J. (2016) ELMO1 Protects Renal Structure and Ultrafiltration in Kidney Development and Under Diabetic Conditions. Sci Rep. 6, 37172.
28. Shimazaki, A., Tanaka, Y., Shinosaki, T., Ikeda, M., Watada, H., Hirose, T., Kawamori, R., and Maeda, S. (2006) ELMO1 Increases Expression of Extracellular Matrix Proteins and Inhibits Cell Adhesion to ECMs. Kidney Int. 70, 1769-1776.
29. Hathaway, C. K., Chang, A. S., Grant, R., Kim, H. S., Madden, V. J., Bagnell, C. R.,Jr, Jennette, J. C., Smithies, O., and Kakoki, M. (2016) High Elmo1 Expression Aggravates and Low Elmo1 Expression Prevents Diabetic Nephropathy. Proc Natl Acad Sci U S A. 113, 2218-2222.
30. Mehrabzadeh, M., Pasalar, P., Karimi, M., Abdollahi, M., Daneshpour, M., Asadolahpour, E., and Razi, F. (2016) Association between ELMO1 Gene Polymorphisms and Diabetic Nephropathy in an Iranian Population. J Diabetes Metab Disord. 15, 43-016-0265-3. eCollection 2015.
31. Bodhini, D., Chidambaram, M., Liju, S., Revathi, B., Laasya, D., Sathish, N., Kanthimathi, S., Ghosh, S., Anjana, R. M., Mohan, V., and Radha, V. (2016) Association of rs11643718 SLC12A3 and rs741301 ELMO1 Variants with Diabetic Nephropathy in South Indian Population. Ann Hum Genet. 80, 336-341.
|Science Writers||Anne Murray|
|Authors||Xue Zhong, Jin Huk Choi, Evan Nair-Gill, Jianhui Wang, and Bruce Beutler|
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