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HAVCR1
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	5DZO, 5F70
Identifiers
Aliases	HAVCR1, HAVCR, HAVCR-1, KIM-1, KIM1, TIM, TIM-1, TIM1, TIMD-1, TIMD1, CD365, hepatitis A virus cellular receptor 1
External IDs	OMIM: 606518; MGI: 2159680; HomoloGene: 134424; GeneCards: HAVCR1; OMA:HAVCR1 - orthologs
Gene location (Human)
Chr.	Chromosome 5 (human)
End	157,059,119 bp
Gene location (Mouse)
Chr.	Chromosome 11 (mouse)
End	46,670,405 bp
RNA expression pattern
	Top expressed in
	testicle; ; human kidney; ; rectum; ; gonad; ; granulocyte; ; epithelium of colon; ; lymph node; ; blood; ; endometrium; ; islet of Langerhans;
	Top expressed in
	blastocyst; ; zygote; ; decidua; ; morula; ; secondary oocyte; ; mesenteric lymph nodes; ; embryo; ; primary oocyte; ; proximal tubule; ; spleen;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	virus receptor activity;
Cellular component	integral component of membrane; motile cilium; membrane;
Biological process	viral process; viral entry into host cell;
	Sources:Amigo / QuickGO
Orthologs
	26762
	171283
	ENSG00000113249
	ENSMUSG00000040405
	Q96D42
	Q5QNS5
	NM_001099414; NM_001173393; NM_001308156; NM_012206
	NM_001166631; NM_001166632; NM_134248
	NP_001166864; NP_001295085; NP_036338
	NP_001160103; NP_001160104; NP_599009
	Wikidata
View/Edit Human	View/Edit Mouse

Hepatitis A virus cellular receptor 1 (HAVcr-1) also known as T-cell immunoglobulin and mucin domain 1 (TIM-1) is a protein that in humans is encoded by the HAVCR1 gene.^[5]^[6]^[7]

It is also known as KIM-1 Kidney Injury Molecule -1, which is a type 1 transmembrane protein the most highly upregulated in injured kidneys by various types of insults.^[8] Its upregulation during renal injury has been found in the kidneys of the vertebrates such as Zebrafish and humans.

The hepatitis A virus cellular receptor 1 (HAVCR1/TIM-1), is a member of the TIM (T cell transmembrane, immunoglobulin, and mucin) gene family, which plays critical roles in regulating immune cell activity especially regarding the host response to viral infection. TIM-1 is also involved in allergic response, asthma, and transplant tolerance.

The TIM gene family was first cloned from the mouse model of asthma in 2001.^[6] Subsequently, it was demonstrated that members of the TIM gene family including TIM-1 participate in host immune response. The mouse TIM gene family contains eight members (TIM-1-8) while only three TIM genes (TIM-1, TIM-3, and TIM-4) have been identified in humans.

Structure and function

TIM genes belong to type I cell-surface glycoproteins, which include an N-terminal immunoglobulin (Ig)-like domain, a mucin domain with distinct length, a single transmembrane domain, and a C-terminal short cytoplasmic tail. The localization and functions of TIM genes are divergent between each member. TIM-1 is preferentially expressed on Th2 cells and has been identified as a stimulatory molecule for T-cell activation.^[9] TIM-3 is preferentially expressed on Th1 and Tc1 cells and function as an inhibitory molecule, which mediated apoptosis of Th1 and Tc1 cells.^[10] TIM-4 is preferentially expressed on antigen-presenting cells, modulating the phagocytosis of apoptotic cells by interacting with phosphatidylserine (PS) exposed on apoptotic cell surface.^[11]

Role in viral infection

TIM genes are also involved in host-virus interaction. As receptors for phosphatidylserine, TIM proteins bind many families of viruses [filovirus, flavivirus, New World arenavirus and alphavirus] that include viruses such as dengue and ebola. Entry of Lassa fever virus, influenza A virus, and SARS coronavirus were not affected by TIM-1 expression. TIM-1 and TIM-4 enhanced viral entry more than TIM-3.^[12]

Hepatitis A

TIM-1 has been identified as an attachment factor for exosome-packaged hepatitis A virus (HAV).^[13] Infectious HAV-containing exosomes are internalized by HAVCR1, but true entry into the cytosol is achieved through fusion with NPC1. It has also been shown that non-exosomal HAV (encapsidated) infection occurs independent of HAVCR1 expression. By using an expression cloning library, IgA has been demonstrated as a specific ligand of TIM-1. The association of TIM-1 and IgA was able to enhance the virus-receptor interaction.^[14]

Ebola

Recently, TIM-1 has been shown to be a receptor or cofactor for Ebola virus entry. TIM-1 binds to Ebola virus glycoproteins (GP) and mediates Ebola virus cellular entry by increasing Ebola virus infectivity in cell lines with a low susceptibility. Moreover, reducing expression of endogenous TIM-1 in highly permissive cell lines decreased Ebola virus infectivity.^[15] Furthermore, TIM-1 IgV domain specific antibody ARD5 inhibited Ebola virus infectivity, indicating that TIM-1 was critical for Ebola virus entry. Also, TIM-1 expression on human mucosal epithelial cells from the trachea, cornea and conjunctiva demonstrated the correlation of TIM-1 expression feature and viral entry routes.

Dengue

TIM-1 has been identified as a cellular factor for Dengue virus entry by overexpression of TIM-1 on poorly susceptible cell lines for Dengue virus infection. TIM-1 enhanced dengue virus infectivity by 500-fold, particularly increased virus internalization. TIM-1 directly interacted with Dengue virus particle by recognizing PS on the virion surface.^[16] In addition, the Dengue virus susceptibility of different cell lines was consistent with endogenous expression level of TIM-1 gene in such cell lines, suggesting that TIM-1 is crucial for Dengue virus entry.

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000113249 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000040405 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Feigelstock D, Thompson P, Mattoo P, Zhang Y, Kaplan GG (Aug 1998). "The human homolog of HAVcr-1 codes for a hepatitis A virus cellular receptor". Journal of Virology. 72 (8): 6621–6628. doi:10.1128/JVI.72.8.6621-6628.1998. PMC 109848. PMID 9658108.
^ ^a ^b McIntire JJ, Umetsu SE, Akbari O, Potter M, Kuchroo VK, Barsh GS, Freeman GJ, Umetsu DT, DeKruyff RH (November 2001). "Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family". Nature Immunology. 2 (12): 1109–1116. doi:10.1038/ni739. PMID 11725301. S2CID 7243788.
^ "Entrez Gene: HAVCR1 hepatitis A virus cellular receptor 1".
^ Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV (July 2002). "Kidney Injury Molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury". Kidney International. 62 (1): 237–244. doi:10.1046/j.1523-1755.2002.00433.x. ISSN 0085-2538. PMID 12081583.
^ Umetsu SE, Lee WL, McIntire JJ, Downey L, Sanjanwala B, Akbari O, Berry GJ, Nagumo H, Freeman GJ, Umetsu DT, DeKruyff RH (May 2005). "TIM-1 induces T cell activation and inhibits the development of peripheral tolerance". Nature Immunology. 6 (5): 447–454. doi:10.1038/ni1186. PMID 15793575. S2CID 29071338.
^ Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB, Kuchroo VK (December 2005). "The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity". Nature Immunology. 6 (12): 1245–1252. doi:10.1038/ni1271. PMID 16286920. S2CID 24886582.
^ 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): 927–940. doi:10.1016/j.immuni.2007.11.011. PMC 2757006. PMID 18082433.
^ Jemielity S, Wang JJ, Chan YK, Ahmed AA, Li W, Monahan S, Bu X, Farzan M, Freeman GJ, Umetsu DT, Dekruyff RH, Choe H (March 2013). "TIM-family proteins promote infection of multiple enveloped viruses through virion-associated phosphatidylserine". PLOS Pathogens. 9 (3): e1003232. doi:10.1371/journal.ppat.1003232. PMC 3610696. PMID 23555248.
^ Costafreda MI, Abbasi A, Lu H, Kaplan G (September 2020). "Exosome mimicry by a HAVCR1-NPC1 pathway of endosomal fusion mediates hepatitis A virus infection". Nature Microbiology. 5 (9): 1096–1106. doi:10.1038/s41564-020-0740-y. ISSN 2058-5276. PMC 7483988. PMID 32541946.
^ Tami C, Silberstein E, Manangeeswaran M, Freeman GJ, Umetsu SE, DeKruyff RH, Umetsu DT, Kaplan GG (April 2007). "Immunoglobulin A (IgA) is a natural ligand of hepatitis A virus cellular receptor 1 (HAVCR1), and the association of IgA with HAVCR1 enhances virus-receptor interactions". Journal of Virology. 81 (7): 3437–3446. doi:10.1128/JVI.01585-06. PMC 1866050. PMID 17229699.
^ Kondratowicz AS, Lennemann NJ, Sinn PL, Davey RA, Hunt CL, Moller-Tank S, Meyerholz DK, Rennert P, Mullins RF, Brindley M, Sandersfeld LM, Quinn K, Weller M, McCray PB, Chiorini J, Maury W (May 2011). "T-cell immunoglobulin and mucin domain 1 (TIM-1) is a receptor for Zaire Ebolavirus and Lake Victoria Marburgvirus". Proceedings of the National Academy of Sciences, USA. 108 (20): 8426–8431. Bibcode:2011PNAS..108.8426K. doi:10.1073/pnas.1019030108. PMC 3100998. PMID 21536871.
^ Meertens L, Carnec X, Lecoin MP, Ramdasi R, Guivel-Benhassine F, Lew E, Lemke G, Schwartz O, Amara A (October 2012). "The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry". Cell Host Microbe. 12 (4): 544–557. doi:10.1016/j.chom.2012.08.009. PMC 3572209. PMID 23084921.

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McIntire JJ, Umetsu DT, DeKruyff RH (2004). "TIM-1, a novel allergy and asthma susceptibility gene". Springer Seminars in Immunopathology. 25 (3–4): 335–348. doi:10.1007/s00281-003-0141-3. PMID 15007635. S2CID 24297235.
Thompson P, Lu J, Kaplan GG (1998). "The Cys-rich region of hepatitis A virus cellular receptor 1 is required for binding of hepatitis A virus and protective monoclonal antibody 190/4". Journal of Virology. 72 (5): 3751–3761. doi:10.1128/JVI.72.5.3751-3761.1998. PMC 109597. PMID 9557657.
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