* 609962

C-TYPE LECTIN DOMAIN FAMILY 4, MEMBER E; CLEC4E


Alternative titles; symbols

MACROPHAGE-INDUCIBLE C-TYPE LECTIN; MINCLE


HGNC Approved Gene Symbol: CLEC4E

Cytogenetic location: 12p13.31     Genomic coordinates (GRCh38): 12:8,533,275-8,540,905 (from NCBI)


TEXT

Description

Calcium-dependent (C-type) lectins, such as CLEC4E, contain carbohydrate recognition domains (CRDs) that are involved in pathogen recognition and cell-cell interactions. C-type lectins are expressed on the surface of macrophages and other antigen-presenting cells and play roles in the functions of these cells (Matsumoto et al., 1999; Arce et al., 2004).


Cloning and Expression

By screening a subtraction library constructed from wildtype and Nfil6 (CEBPB; 189965)-deficient mouse peritoneal macrophages to identify downstream targets of Nfil6, followed by degenerative PCR and RACE of a lipopolysaccharide-stimulated human monocyte/macrophage cell line, Matsumoto et al. (1999) cloned CLEC4E, which they termed MINCLE. The predicted 219-amino acid human protein shares 67% identity with the mouse protein. MINCLE contains 2 potential cytoplasmic protein kinase C (see 176960) phosphorylation sites, followed by a 141-amino acid CRD with 2 potential extracellular N-glycosylation sites. Expression analysis suggested that MINCLE is expressed only in monocytes.


Mapping

By genomic sequence analysis, Arce et al. (2004) mapped the CLEC4E gene to chromosome 12p13, centromeric to the CLEC4D gene (609964). Matsumoto et al. (1999) mapped the mouse Clec4e gene to chromosome 6.


Gene Function

By mutation and luciferase reporter analyses, Matsumoto et al. (1999) found that expression of mouse Mincle was induced by Nfil6 after it bound to the Mincle promoter region. Matsumoto et al. (1999) concluded that MINCLE expression is strongly induced in response to inflammatory stimuli under the regulation of NFIL6 in macrophages.

By screening pathogenic fungi with a cell line expressing MINCLE, Yamasaki et al. (2009) found that MINCLE specifically interacted with Malassezia species, which cause the skin diseases tinea versicolor and atopic dermatitis, as well as fatal sepsis. Mutation analysis showed that Malassezia interacted with the mannose-binding motif of MINCLE. Glycoconjugate microarray analysis indicated that MINCLE bound alpha-mannose but not mannan, suggesting that the geometry of alpha-mannosyl residues on Malassezia species is recognized by MINCLE and distinguishes them from Candida, Aspergillus, and other fungal species. Malassezia-activated macrophages produced TNF (191160) and other inflammatory cytokines and chemokines. Macrophages from mice lacking Mincle showed impaired cytokine/chemokine production, and the mutant mice had diminished inflammatory responses. Yamasaki et al. (2009) concluded that MINCLE is the first reported receptor for Malassezia species and has a crucial role in immune responses to these fungi.

Miyake et al. (2013) noted that MINCLE is an activating receptor that couples with the FcR gamma chain (see FCER1G; 147139) and recognizes the potent mycobacterial adjuvant trehalose-6,6-prime-dimycolate (TDM), also called cord factor. By immunoblot and in situ hybridization analyses, they demonstrated that expression of Mincle was undetectable in mouse lung and bone marrow-derived dendritic cells until upregulated by TDM exposure, suggesting that another TDM receptor may promote the initial induction of Mincle. Expression of Mincle was also dependent on Fcer1g. Sequence analysis using the anti-Mincle antibody binding site (VEGQW) within the CRD of Mincle showed that the site was shared by mouse Mcl (CLEC4D; 609964), a type II transmembrane protein that was also expressed in lung. Both mouse and human MCL bound TDM. Mcl, unlike Mincle, was constitutively expressed in mouse myeloid cells. Exposure to TDM upregulated Mincle, whereas Mcl expression remained steady. Flow cytometric and coimmunoprecipitation analyses demonstrated that, like Mincle, Mcl expression was dependent on FcR-gamma. Reporter gene assays showed that mouse Mcl functioned as an FcR-gamma-coupled activating receptor in response TDM.

Hattori et al. (2014) extended previous findings concerning the interaction of TDM with MINCLE to another mycobacterial lipidic compound, glycerol monomycolate (GroMM). Cells expressing human MINCLE reacted to both TDM and GroMM, whereas cells expressing murine Mincle only reacted to TDM. Domain swapping analysis showed that the ectodomain of human MINCLE, but not that of murine Mincle, interacted with GroMM. Site-directed mutagenesis analyses revealed that residues 174 to 176 and 195 to 196 were involved in GroMM recognition. Macrophages from transgenic mice lacking murine Mincle but expressing human MINCLE were activated by GroMM and produced inflammatory cytokines, such as Tnf. In contrast, nontransgenic mice expressing murine Mincle failed to generate an inflammatory response to GroMM. Injection of liposomes containing GroMM into mouse skin resulted in local inflammatory responses to MINCLE in transgenic mice, but not in nontransgenic mice. Hattori et al. (2014) concluded that GroMM is a unique ligand for human MINCLE that is not recognized by mouse Mincle.

Seifert et al. (2016) reported that the principal components of the necrosome, receptor-interacting proteins RIP1 (603453) and RIP3 (605817), are highly expressed in pancreatic ductal adenocarcinoma (PDA) and are further upregulated by the chemotherapy drug gemcitabine. Cytoplasmic SF3B3 (605592), a subunit of the histone deacetylase complex, was expressed in PDA in a RIP1/RIP3-dependent manner, and MINCLE, its cognate receptor, was upregulated in tumor-infiltrating myeloid cells. Ligation of MINCLE by SF3B3 promoted oncogenesis, whereas deletion of MINCLE protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumor microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or MINCLE is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or MINCLE signaling, were reprogrammed into indispensable mediators of antitumor immunity in the absence of RIP3 or MINCLE. Seifert et al. (2016) concluded that their work described parallel networks of necroptosis-induced CXCL1 and MINCLE signaling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.


Animal Model

Miyake et al. (2013) generated healthy Mcl-deficient mice and found that their bone marrow-derived dendritic cells, like those from mice deficient in Fcer1g or Mincle, were severely impaired in TDM-induced cytokine production. Injection of TDM was lethal for wildtype mice. However, lethality, which was associated with lung inflammation and granuloma formation, was delayed and reduced in mice lacking Mcl, and mice lacking Fcer1g or Mincle were completely resistant to TDM injection. Mincle expression in response to TDM was suppressed in Mcl -/- cells. TDM-induced acquired immune responses, such as experimental autoimmune encephalomyelitis, were almost completely dependent on Mcl, but not on Mincle.


REFERENCES

  1. Arce, I., Martinez-Munoz, L., Roda-Navarro, P., Fernandez-Ruiz, E. The human C-type lectin CLECSF8 is a novel monocyte/macrophage endocytic receptor. Europ. J. Immun. 34: 210-220, 2004. [PubMed: 14971047, related citations] [Full Text]

  2. Hattori, Y., Morita, D., Fujiwara, N., Mori, D., Nakamura, T., Harashima, H., Yamasaki, S., Sugita, M. Glycerol monomycolate is a novel ligand for the human, but not mouse macrophage inducible C-type lectin, Mincle. J. Biol. Chem. 289: 15405-15412, 2014. [PubMed: 24733387, images, related citations] [Full Text]

  3. Matsumoto, M., Tanaka, T., Kaisho, T., Sanjo, H., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Akira, S. A novel LPS-inducible C-type lectin is a transcriptional target of NF-IL6 in macrophages. J. Immun. 163: 5039-5048, 1999. [PubMed: 10528209, related citations]

  4. Miyake, Y., Toyonaga, K., Mori, D., Kakuta, S., Hoshino, Y., Oyamada, A., Yamada, H., Ono, K., Suyama, M., Iwakura, Y., Yoshikai, Y., Yamasaki, S. C-type lectin MCL is an FcR-gamma-coupled receptor that mediates the adjuvanticity of mycobacterial cord factor. Immunity 38: 1050-1062, 2013. [PubMed: 23602766, related citations] [Full Text]

  5. Seifert, L., Werba, G., Tiwari, S., Giao Ly, N. N., Alothman, S., Alqunaibit, D., Avanzi, A., Barilla, R., Daley, D., Greco, S. H., Torres-Hernandez, A., Pergamo, M., and 10 others. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 532: 245-249, 2016. Note: Erratum: Nature 591: E28, 2021. [PubMed: 27049944, related citations] [Full Text]

  6. Yamasaki, S., Matsumoto, M., Takeuchi, O., Matsuzawa, T., Ishikawa, E., Sakuma, M., Tateno, H., Uno, J., Hirabayashi, J., Mikami, Y., Takeda, K., Akira, S., Saito, T. C-type lectin Mincle is an activating receptor for pathogenic fungus, Malassezia. Proc. Nat. Acad. Sci. 106: 1897-1902, 2009. [PubMed: 19171887, images, related citations] [Full Text]


Ada Hamosh - updated : 09/29/2016
Paul J. Converse - updated : 6/4/2014
Paul J. Converse - updated : 9/12/2013
Paul J. Converse - updated : 7/7/2009
Creation Date:
Paul J. Converse : 3/15/2006
carol : 04/23/2021
alopez : 09/30/2016
alopez : 09/29/2016
mgross : 06/11/2014
mcolton : 6/4/2014
mgross : 9/12/2013
mgross : 7/8/2009
terry : 7/7/2009
mgross : 3/21/2006
mgross : 3/16/2006
mgross : 3/15/2006

* 609962

C-TYPE LECTIN DOMAIN FAMILY 4, MEMBER E; CLEC4E


Alternative titles; symbols

MACROPHAGE-INDUCIBLE C-TYPE LECTIN; MINCLE


HGNC Approved Gene Symbol: CLEC4E

Cytogenetic location: 12p13.31     Genomic coordinates (GRCh38): 12:8,533,275-8,540,905 (from NCBI)


TEXT

Description

Calcium-dependent (C-type) lectins, such as CLEC4E, contain carbohydrate recognition domains (CRDs) that are involved in pathogen recognition and cell-cell interactions. C-type lectins are expressed on the surface of macrophages and other antigen-presenting cells and play roles in the functions of these cells (Matsumoto et al., 1999; Arce et al., 2004).


Cloning and Expression

By screening a subtraction library constructed from wildtype and Nfil6 (CEBPB; 189965)-deficient mouse peritoneal macrophages to identify downstream targets of Nfil6, followed by degenerative PCR and RACE of a lipopolysaccharide-stimulated human monocyte/macrophage cell line, Matsumoto et al. (1999) cloned CLEC4E, which they termed MINCLE. The predicted 219-amino acid human protein shares 67% identity with the mouse protein. MINCLE contains 2 potential cytoplasmic protein kinase C (see 176960) phosphorylation sites, followed by a 141-amino acid CRD with 2 potential extracellular N-glycosylation sites. Expression analysis suggested that MINCLE is expressed only in monocytes.


Mapping

By genomic sequence analysis, Arce et al. (2004) mapped the CLEC4E gene to chromosome 12p13, centromeric to the CLEC4D gene (609964). Matsumoto et al. (1999) mapped the mouse Clec4e gene to chromosome 6.


Gene Function

By mutation and luciferase reporter analyses, Matsumoto et al. (1999) found that expression of mouse Mincle was induced by Nfil6 after it bound to the Mincle promoter region. Matsumoto et al. (1999) concluded that MINCLE expression is strongly induced in response to inflammatory stimuli under the regulation of NFIL6 in macrophages.

By screening pathogenic fungi with a cell line expressing MINCLE, Yamasaki et al. (2009) found that MINCLE specifically interacted with Malassezia species, which cause the skin diseases tinea versicolor and atopic dermatitis, as well as fatal sepsis. Mutation analysis showed that Malassezia interacted with the mannose-binding motif of MINCLE. Glycoconjugate microarray analysis indicated that MINCLE bound alpha-mannose but not mannan, suggesting that the geometry of alpha-mannosyl residues on Malassezia species is recognized by MINCLE and distinguishes them from Candida, Aspergillus, and other fungal species. Malassezia-activated macrophages produced TNF (191160) and other inflammatory cytokines and chemokines. Macrophages from mice lacking Mincle showed impaired cytokine/chemokine production, and the mutant mice had diminished inflammatory responses. Yamasaki et al. (2009) concluded that MINCLE is the first reported receptor for Malassezia species and has a crucial role in immune responses to these fungi.

Miyake et al. (2013) noted that MINCLE is an activating receptor that couples with the FcR gamma chain (see FCER1G; 147139) and recognizes the potent mycobacterial adjuvant trehalose-6,6-prime-dimycolate (TDM), also called cord factor. By immunoblot and in situ hybridization analyses, they demonstrated that expression of Mincle was undetectable in mouse lung and bone marrow-derived dendritic cells until upregulated by TDM exposure, suggesting that another TDM receptor may promote the initial induction of Mincle. Expression of Mincle was also dependent on Fcer1g. Sequence analysis using the anti-Mincle antibody binding site (VEGQW) within the CRD of Mincle showed that the site was shared by mouse Mcl (CLEC4D; 609964), a type II transmembrane protein that was also expressed in lung. Both mouse and human MCL bound TDM. Mcl, unlike Mincle, was constitutively expressed in mouse myeloid cells. Exposure to TDM upregulated Mincle, whereas Mcl expression remained steady. Flow cytometric and coimmunoprecipitation analyses demonstrated that, like Mincle, Mcl expression was dependent on FcR-gamma. Reporter gene assays showed that mouse Mcl functioned as an FcR-gamma-coupled activating receptor in response TDM.

Hattori et al. (2014) extended previous findings concerning the interaction of TDM with MINCLE to another mycobacterial lipidic compound, glycerol monomycolate (GroMM). Cells expressing human MINCLE reacted to both TDM and GroMM, whereas cells expressing murine Mincle only reacted to TDM. Domain swapping analysis showed that the ectodomain of human MINCLE, but not that of murine Mincle, interacted with GroMM. Site-directed mutagenesis analyses revealed that residues 174 to 176 and 195 to 196 were involved in GroMM recognition. Macrophages from transgenic mice lacking murine Mincle but expressing human MINCLE were activated by GroMM and produced inflammatory cytokines, such as Tnf. In contrast, nontransgenic mice expressing murine Mincle failed to generate an inflammatory response to GroMM. Injection of liposomes containing GroMM into mouse skin resulted in local inflammatory responses to MINCLE in transgenic mice, but not in nontransgenic mice. Hattori et al. (2014) concluded that GroMM is a unique ligand for human MINCLE that is not recognized by mouse Mincle.

Seifert et al. (2016) reported that the principal components of the necrosome, receptor-interacting proteins RIP1 (603453) and RIP3 (605817), are highly expressed in pancreatic ductal adenocarcinoma (PDA) and are further upregulated by the chemotherapy drug gemcitabine. Cytoplasmic SF3B3 (605592), a subunit of the histone deacetylase complex, was expressed in PDA in a RIP1/RIP3-dependent manner, and MINCLE, its cognate receptor, was upregulated in tumor-infiltrating myeloid cells. Ligation of MINCLE by SF3B3 promoted oncogenesis, whereas deletion of MINCLE protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumor microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or MINCLE is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or MINCLE signaling, were reprogrammed into indispensable mediators of antitumor immunity in the absence of RIP3 or MINCLE. Seifert et al. (2016) concluded that their work described parallel networks of necroptosis-induced CXCL1 and MINCLE signaling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.


Animal Model

Miyake et al. (2013) generated healthy Mcl-deficient mice and found that their bone marrow-derived dendritic cells, like those from mice deficient in Fcer1g or Mincle, were severely impaired in TDM-induced cytokine production. Injection of TDM was lethal for wildtype mice. However, lethality, which was associated with lung inflammation and granuloma formation, was delayed and reduced in mice lacking Mcl, and mice lacking Fcer1g or Mincle were completely resistant to TDM injection. Mincle expression in response to TDM was suppressed in Mcl -/- cells. TDM-induced acquired immune responses, such as experimental autoimmune encephalomyelitis, were almost completely dependent on Mcl, but not on Mincle.


REFERENCES

  1. Arce, I., Martinez-Munoz, L., Roda-Navarro, P., Fernandez-Ruiz, E. The human C-type lectin CLECSF8 is a novel monocyte/macrophage endocytic receptor. Europ. J. Immun. 34: 210-220, 2004. [PubMed: 14971047] [Full Text: https://doi.org/10.1002/eji.200324230]

  2. Hattori, Y., Morita, D., Fujiwara, N., Mori, D., Nakamura, T., Harashima, H., Yamasaki, S., Sugita, M. Glycerol monomycolate is a novel ligand for the human, but not mouse macrophage inducible C-type lectin, Mincle. J. Biol. Chem. 289: 15405-15412, 2014. [PubMed: 24733387] [Full Text: https://doi.org/10.1074/jbc.M114.566489]

  3. Matsumoto, M., Tanaka, T., Kaisho, T., Sanjo, H., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Akira, S. A novel LPS-inducible C-type lectin is a transcriptional target of NF-IL6 in macrophages. J. Immun. 163: 5039-5048, 1999. [PubMed: 10528209]

  4. Miyake, Y., Toyonaga, K., Mori, D., Kakuta, S., Hoshino, Y., Oyamada, A., Yamada, H., Ono, K., Suyama, M., Iwakura, Y., Yoshikai, Y., Yamasaki, S. C-type lectin MCL is an FcR-gamma-coupled receptor that mediates the adjuvanticity of mycobacterial cord factor. Immunity 38: 1050-1062, 2013. [PubMed: 23602766] [Full Text: https://doi.org/10.1016/j.immuni.2013.03.010]

  5. Seifert, L., Werba, G., Tiwari, S., Giao Ly, N. N., Alothman, S., Alqunaibit, D., Avanzi, A., Barilla, R., Daley, D., Greco, S. H., Torres-Hernandez, A., Pergamo, M., and 10 others. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 532: 245-249, 2016. Note: Erratum: Nature 591: E28, 2021. [PubMed: 27049944] [Full Text: https://doi.org/10.1038/nature17403]

  6. Yamasaki, S., Matsumoto, M., Takeuchi, O., Matsuzawa, T., Ishikawa, E., Sakuma, M., Tateno, H., Uno, J., Hirabayashi, J., Mikami, Y., Takeda, K., Akira, S., Saito, T. C-type lectin Mincle is an activating receptor for pathogenic fungus, Malassezia. Proc. Nat. Acad. Sci. 106: 1897-1902, 2009. [PubMed: 19171887] [Full Text: https://doi.org/10.1073/pnas.0805177106]


Contributors:
Ada Hamosh - updated : 09/29/2016
Paul J. Converse - updated : 6/4/2014
Paul J. Converse - updated : 9/12/2013
Paul J. Converse - updated : 7/7/2009

Creation Date:
Paul J. Converse : 3/15/2006

Edit History:
carol : 04/23/2021
alopez : 09/30/2016
alopez : 09/29/2016
mgross : 06/11/2014
mcolton : 6/4/2014
mgross : 9/12/2013
mgross : 7/8/2009
terry : 7/7/2009
mgross : 3/21/2006
mgross : 3/16/2006
mgross : 3/15/2006