TIMD4

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 phosphatidylserin.[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 tyrosin-phosphorylation motif in its intracellular tail domain.[7]

TIMD4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 5F7H, 5DZN, 5F7F
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
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q33.3 Start 156,919,292 bp[1] End 156,963,226 bp[1]
Gene location (Mouse) Chr. Chromosome 11 (mouse)[2] Band 11|11 B1.1 Start 46,810,800 bp[2] End 46,844,332 bp[2]
Orthologs
Species	Human	Mouse
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: 46.81 – 46.84 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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 phosphatidylserin. Its phosphatidylserin binding however does not mediate signalling instead it works more as a tethering receptor.[9] Its phosphatidylserin binding properties also play an important role in removal of apoptotic cells.[10] Moreover recognition of phosphatidylserin also helps to control adaptive immune system by clearing phosphatidylserin 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 was also recognized as a factor in tumor development. For example it was shown that TIM-4 promotes colorectal cancer by activating angiogenesis and recruiting tumor associated macrophages.[18] 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.[19] Therefore there are studies using the blockade of TIM-4 as a complementary therapy for cancer treatment.[20]

References

1. GRCh38: Ensembl release 89: ENSG00000145850 - Ensembl, May 2017
2. 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. 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. Tan X, Zhang Z, Yao H, Shen L (November 2018). "Tim-4 promotes the growth of colorectal cancer by activating angiogenesis and recruiting tumor-associated macrophages via the PI3K/AKT/mTOR signaling pathway". Cancer Letters. 436: 119–128. doi:10.1016/j.canlet.2018.08.012. PMID 30118845.
19. 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.
20. 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. PMID 23143694. S2CID 19381873.