TIMD4

Last updated
TIMD4
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TIMD4 , SMUCKLER, TIM4, T-cell immunoglobulin and mucin domain containing 4, T cell immunoglobulin and mucin domain containing 4
External IDs OMIM: 610096; MGI: 2445125; HomoloGene: 51381; GeneCards: TIMD4; OMA:TIMD4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

91937

276891

Ensembl

ENSG00000145850

ENSMUSG00000055546

UniProt

Q96H15

Q6U7R4

RefSeq (mRNA)

NM_001146726
NM_138379

NM_178759

RefSeq (protein)

NP_001140198
NP_612388

NP_848874

Location (UCSC) Chr 5: 156.92 – 156.96 Mb Chr 11: 46.7 – 46.74 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

T-cell immunoglobulin and mucin domain containing 4 (TIMD-4) also known as T-cell membrane protein 4 (TIM-4) is a protein in humans that is encoded by the TIMD4 gene. [5] TIM-4 genes are in mouse present on chromosome 11B1.1 and in humans on chromosome 5q33.2. TIM-4 contains IgV domain with integrin-binding site as well as a unique metal-ion-dependent ligand binding site for phosphatidylserine. [6] TIM-4 also contains mucin domain with high levels of O-glycosylation. In comparison to other TIM proteins (such as TIM-1, TIM-2...) it does not contain a tyrosine-phosphorylation motif in its intracellular tail domain. [7]

Contents

TIM-4 expression and function

Unlike other TIMs that are mainly expressed on T cells TIM-4 is expressed on APCs such as dendritic cells or macrophages. [7] TIM-4 serves as a ligand for TIM-1 [8] but also as a receptor for phosphatidylserine. Its phosphatidylserine binding however does not mediate signalling instead it works more as a tethering receptor. [9] Its phosphatidylserine binding properties also play an important role in removal of apoptotic cells. [10] Moreover recognition of phosphatidylserine also helps to control adaptive immune system by clearing phosphatidylserine expressing apoptotic T cells. That leads to the regulation of antigen specific memory T cells. [11] TIM-4 is also able to inhibit naive T cells by non-TIM-1 receptor binding [12] but once T cells are active TIM-4 works as positive regulator helping to maintain their activity. [13] [14] TIM-4 expression on macrophages plays an important role in their homeostatic maintenance. [15]

Role in diseases and possible clinical use

It was shown that TIM-4 plays a role in Th2 development. As such it plays a role in the development of allergies and might be a target for future therapies. [16] [17] TIM-4 also mediates autophagy at the site of tumor, which leads to reduced antigen presentation leading to increased toleration of tumor by the immune system. [18] Therefore there are studies using the blockade of TIM-4 as a complementary therapy for cancer treatment. [19]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000145850 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000055546 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: T-cell immunoglobulin and mucin domain containing 4".
  6. ↑ Santiago C, Ballesteros A, Martínez-Muñoz L, Mellado M, Kaplan GG, Freeman GJ, Casasnovas JM (December 2007). "Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds". Immunity. 27 (6): 941–51. doi:10.1016/j.immuni.2007.11.008. PMC   2330274 . PMID   18083575.
  7. 1 2 Meyers JH, Sabatos CA, Chakravarti S, Kuchroo VK (August 2005). "The TIM gene family regulates autoimmune and allergic diseases". Trends in Molecular Medicine. 11 (8): 362–9. doi:10.1016/j.molmed.2005.06.008. PMID   16002337.
  8. ↑ "Dogmas, paradigms and proving hypotheses". Nature Immunology. 11 (6): 455. June 2010. doi: 10.1038/ni0610-455 . PMID   20485268.
  9. ↑ Park D, Hochreiter-Hufford A, Ravichandran KS (February 2009). "The phosphatidylserine receptor TIM-4 does not mediate direct signaling". Current Biology. 19 (4): 346–51. doi: 10.1016/j.cub.2009.01.042 . PMID   19217291. S2CID   17015987.
  10. ↑ Kobayashi N, Karisola P, Peña-Cruz V, Dorfman DM, Jinushi M, Umetsu SE, Butte MJ, Nagumo H, Chernova I, Zhu B, Sharpe AH, Ito S, Dranoff G, Kaplan GG, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ (December 2007). "TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells". Immunity. 27 (6): 927–40. doi:10.1016/j.immuni.2007.11.011. PMC   2757006 . PMID   18082433.
  11. ↑ Albacker LA, Karisola P, Chang YJ, Umetsu SE, Zhou M, Akbari O, Kobayashi N, Baumgarth N, Freeman GJ, Umetsu DT, DeKruyff RH (December 2010). "TIM-4, a receptor for phosphatidylserine, controls adaptive immunity by regulating the removal of antigen-specific T cells". Journal of Immunology. 185 (11): 6839–49. doi:10.4049/jimmunol.1001360. PMC   3153437 . PMID   21037090.
  12. ↑ Rodriguez-Manzanet R, DeKruyff R, Kuchroo VK, Umetsu DT (May 2009). "The costimulatory role of TIM molecules". Immunological Reviews. 229 (1): 259–70. doi:10.1111/j.1600-065x.2009.00772.x. PMC   3217781 . PMID   19426227.
  13. ↑ Mizui M, Shikina T, Arase H, Suzuki K, Yasui T, Rennert PD, Kumanogoh A, Kikutani H (May 2008). "Bimodal regulation of T cell-mediated immune responses by TIM-4". International Immunology. 20 (5): 695–708. doi: 10.1093/intimm/dxn029 . PMID   18367551.
  14. ↑ Rodriguez-Manzanet, R.; Meyers, J. H.; Balasubramanian, S.; Slavik, J.; Kassam, N.; Dardalhon, V.; Greenfield, E. A.; Anderson, A. C.; Sobel, R. A. (2008-04-01). "TIM-4 Expressed on APCs Induces T Cell Expansion and Survival". The Journal of Immunology. 180 (7): 4706–4713. doi: 10.4049/jimmunol.180.7.4706 . ISSN   0022-1767. PMC   2948965 . PMID   18354194.
  15. ↑ Wong K, Valdez PA, Tan C, Yeh S, Hongo JA, Ouyang W (May 2010). "Phosphatidylserine receptor Tim-4 is essential for the maintenance of the homeostatic state of resident peritoneal macrophages". Proceedings of the National Academy of Sciences of the United States of America. 107 (19): 8712–7. Bibcode:2010PNAS..107.8712W. doi: 10.1073/pnas.0910929107 . PMC   2889355 . PMID   20421466.
  16. ↑ Yang PC, Xing Z, Berin CM, Soderholm JD, Feng BS, Wu L, Yeh C (November 2007). "TIM-4 expressed by mucosal dendritic cells plays a critical role in food antigen-specific Th2 differentiation and intestinal allergy". Gastroenterology. 133 (5): 1522–33. doi: 10.1053/j.gastro.2007.08.006 . PMID   17915221.
  17. ↑ Feng BS, Chen X, He SH, Zheng PY, Foster J, Xing Z, Bienenstock J, Yang PC (July 2008). "Disruption of T-cell immunoglobulin and mucin domain molecule (TIM)-1/TIM4 interaction as a therapeutic strategy in a dendritic cell-induced peanut allergy model". The Journal of Allergy and Clinical Immunology. 122 (1): 55–61, 61.e1–7. doi:10.1016/j.jaci.2008.04.036. PMID   18547633.
  18. ↑ Baghdadi M, Yoneda A, Yamashina T, Nagao H, Komohara Y, Nagai S, Akiba H, Foretz M, Yoshiyama H, Kinoshita I, Dosaka-Akita H, Takeya M, Viollet B, Yagita H, Jinushi M (December 2013). "TIM-4 glycoprotein-mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance". Immunity. 39 (6): 1070–81. doi: 10.1016/j.immuni.2013.09.014 . PMID   24315994.
  19. ↑ Baghdadi M, Nagao H, Yoshiyama H, Akiba H, Yagita H, Dosaka-Akita H, Jinushi M (April 2013). "Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas". Cancer Immunology, Immunotherapy. 62 (4): 629–37. doi:10.1007/s00262-012-1371-9. PMC   11029366 . PMID   23143694. S2CID   19381873.


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