HAVCR1

Last updated
HAVCR1
Available structures
PDB Human UniProt search: PDBe RCSB
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 HomoloGene: 134424 GeneCards: HAVCR1
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001099414
NM_001173393
NM_001308156
NM_012206

n/a

RefSeq (protein)

NP_001166864
NP_001295085
NP_036338

n/a

Location (UCSC) Chr 5: 157.03 – 157.06 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

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. [3] [4] [5]

Contents

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. [6] 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. [4] 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. [7] TIM-3 is preferentially expressed on Th1 and Tc1 cells and function as an inhibitory molecule, which mediated apoptosis of Th1 and Tc1 cells. [8] 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. [9]

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. [10]

Hepatitis A

TIM-1 has been identified as an attachment factor for exosome-packaged hepatitis A virus (HAV). [11] 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. [12]

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. [13] 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. [14] 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.

Related Research Articles

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab) is the secreted form of a B cell receptor; the term immunoglobulin (Ig) can refer to either the membrane-bound form or the secreted form of the B cell receptor, but they are, broadly speaking, the same protein, and so the terms are often treated as synonymous. Antibodies are large, Y-shaped proteins belonging to the immunoglobulin superfamily which are used by the immune system to identify and neutralize foreign objects such as bacteria and viruses, including those that cause disease. Antibodies can recognize virtually any size antigen with diverse chemical compositions from molecules. Each antibody recognizes one or more specific antigens. This term literally means "antibody generator", as it is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">Immunoglobulin M</span> One of several isotypes of antibody

Immunoglobulin M (IgM) is the largest of several isotypes of antibodies that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen; causing it to also be called an acute phase antibody. In humans and other mammals that have been studied, plasmablasts in the spleen are the main source of specific IgM production.

<span class="mw-page-title-main">DC-SIGN</span> Protein-coding gene in the species Homo sapiens

DC-SIGN also known as CD209 is a protein which in humans is encoded by the CD209 gene.

V(D)J recombination is the mechanism of somatic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies/immunoglobulins and T cell receptors (TCRs) found in B cells and T cells, respectively. The process is a defining feature of the adaptive immune system.

<span class="mw-page-title-main">CD19</span> Biomarker for B cell lineage

B-lymphocyte antigen CD19, also known as CD19 molecule, B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene CD19. In humans, CD19 is expressed in all B lineage cells. Contrary to some early doubts, human plasma cells do express CD19, as confirmed by others. CD19 plays two major roles in human B cells: on the one hand, it acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane; on the other, it works within the CD19/CD21 complex to decrease the threshold for B cell receptor signaling pathways. Due to its presence on all B cells, it is a biomarker for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia immunotherapies.

CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction. The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC). It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.

The neonatal fragment crystallizable (Fc) receptor is a protein that in humans is encoded by the FCGRT gene. It is an IgG Fc receptor which is similar in structure to the MHC class I molecule and also associates with beta-2-microglobulin. In rodents, FcRn was originally identified as the receptor that transports maternal immunoglobulin G (IgG) from mother to neonatal offspring via mother's milk, leading to its name as the neonatal Fc receptor. In humans, FcRn is present in the placenta where it transports mother's IgG to the growing fetus. FcRn has also been shown to play a role in regulating IgG and serum albumin turnover. Neonatal Fc receptor expression is up-regulated by the proinflammatory cytokine, TNF, and down-regulated by IFN-γ.

<span class="mw-page-title-main">J chain</span> Protein-coding gene in the species Homo sapiens

The Joining (J) chain is a protein component that links monomers of antibodies IgM and IgA to form polymeric antibodies capable of secretion. The J chain is well conserved in the animal kingdom, but its specific functions are yet to be fully understood. It is a 137 residue polypeptide, encoded by the IGJ gene.

<span class="mw-page-title-main">Polymeric immunoglobulin receptor</span> Protein-coding gene in the species Homo sapiens

Polymeric immunoglobulin receptor (pIgR) is a transmembrane protein that in humans is encoded by the PIGR gene. It is an Fc receptor which facilitates the transcytosis of the soluble polymeric isoforms of immunoglobulin A and immunoglobulin M (pIg) and immune complexes. pIgRs are mainly located on the epithelial lining of mucosal surfaces of the gastrointestinal tract. The composition of the receptor is complex, including 6 immunoglobulin-like domains, a transmembrane region, and an intracellular domain. pIgR expression is under the strong regulation of cytokines, hormones, and pathogenic stimuli.

<span class="mw-page-title-main">LILRB1</span> Protein-coding gene in the species Homo sapiens

Leukocyte immunoglobulin-like receptor subfamily B member 1 is a protein that in humans is encoded by the LILRB1 gene.

<span class="mw-page-title-main">Poliovirus receptor-related 1</span> Protein-coding gene in the species Homo sapiens

Poliovirus receptor-related 1 (PVRL1), also known as nectin-1 and CD111 (formerly herpesvirus entry mediator C, HVEC) is a human protein of the immunoglobulin superfamily (IgSF), also considered a member of the nectins. It is a membrane protein with three extracellular immunoglobulin domains, a single transmembrane helix and a cytoplasmic tail. The protein can mediate Ca2+-independent cellular adhesion further characterizing it as IgSF cell adhesion molecule (IgSF CAM).

<span class="mw-page-title-main">LAIR1</span> Protein-coding gene in the species Homo sapiens

Leukocyte-associated immunoglobulin-like receptor 1 is a protein that in humans is encoded by the LAIR1 gene. LAIR1 has also been designated as CD305.

<span class="mw-page-title-main">LILRB2</span> Protein-coding gene in the species Homo sapiens

Leukocyte immunoglobulin-like receptor subfamily B member 2 is a protein that in humans is encoded by the LILRB2 gene.

<span class="mw-page-title-main">LILRB4</span> Protein-coding gene in the species Homo sapiens

Leukocyte immunoglobulin-like receptor subfamily B member 4 is a protein that in humans is encoded by the LILRB4 gene.

<span class="mw-page-title-main">VPREB1</span> Protein-coding gene in the species Homo sapiens

Immunoglobulin iota chain is a protein that in humans is encoded by the VPREB1 gene. VPREB1 has also recently been designated CD179A.

<span class="mw-page-title-main">HAVCR2</span> Protein-coding gene in the species Homo sapiens

Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3)gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells. HAVCR2 receptor is a regulator of the immune response.

<span class="mw-page-title-main">CD79A</span> Mammalian protein found in Homo sapiens

Cluster of differentiation CD79A also known as B-cell antigen receptor complex-associated protein alpha chain and MB-1 membrane glycoprotein, is a protein that in humans is encoded by the CD79A gene.

<span class="mw-page-title-main">CD79B</span> Mammalian protein found in Homo sapiens

CD79b molecule, immunoglobulin-associated beta, also known as CD79B, is a human gene.

<span class="mw-page-title-main">TIMD4</span> Protein-coding gene in the species Homo sapiens

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. 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. TIM-4 also contains mucin domain with high levels of O-glycosylation. In comparison to other TIM proteins it does not contain a tyrosine-phosphorylation motif in its intracellular tail domain.

Transmembrane immunoglobulin and munin domain (TIM) proteins are a family of cell surface immunomodulatory proteins.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000113249 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 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.
  4. 1 2 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.
  5. "Entrez Gene: HAVCR1 hepatitis A virus cellular receptor 1".
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.

Further reading