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HAVCR1

Official Full Name
hepatitis A virus cellular receptor 1
Background
The protein encoded by this gene is a membrane receptor for both human hepatitis A virus (HHAV) and TIMD4. The encoded protein may be involved in the moderation of asthma and allergic diseases. The reference genome represents an allele that retains a MTTVP amino acid segment that confers protection against atopy in HHAV seropositive individuals. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Mar 2010]
Synonyms
HAVCR1; hepatitis A virus cellular receptor 1; TIM; KIM1; TIM1; HAVCR; KIM-1; TIM-1; TIMD1; TIMD-1; HAVCR-1; kidney injury molecule 1; T-cell membrane protein 1; T-cell immunoglobulin mucin receptor 1; T-cell immunoglobulin mucin family member 1; T cell immunoglobin domain and mucin domain protein 1; HAVCR 1; TIM 1; Tim1, TIM-1, Timd1, AI503787, Havcr1; zgc:92647; wu:fb01b10; hepatitis A virus cellular receptor 1 homolog

Recent Research Progress

The HAVCR1 gene codes for a type I transmembrane glycoprotein that contains an extracellular immunoglobulin-like domain. HAVCR1 protein, also known as TIM-1, was first identified as the human hepatitis A virus (HAV) cellular receptor. And the immunoglobulin domain (IgV) of HAVCR1 interacts with HAV which is a small non-enveloped positive-strand RNA virus. HAVCR1 functions as a phospholipid receptor involved in cell entry of several enveloped viruses.

Some studies have shown that HAVCR1 is not essential for eHAV or HAV infection of human hepatoma-derived cells. Some data indicated that HAVCR1-deficient Vero cells showed a modest reduction in quasi-enveloped eHAV (but not naked HAV) attachment and replication. Thus, HAVCR1 facilitates quasi-enveloped eHAV entry in Vero cells, most likely by binding to phosphatidylserine (PtdSer) residues on the eHAV membrane. Moreover, some researchers believed that HAVCR1 may facilitate attachment and entry of quasi-enveloped eHAV into Vero cells but TIMHAVCR1 is not an essential receptor for viruses in these cells. Taken collectively, some researchers conclude that HAVCR1 is not an essential hepatovirus entry factor, although its PtdSer-binding activity may contribute to the spread of quasi-enveloped virus in mice.

One study suggested that HAVCR1 played a role in facilitating hepatitis C virus (HCV) entry into cells. HAVCR1 functions as a pattern recognition receptor (PRR) of damage-associated molecular patterns (DAMPS) by recognizing phosphatidylserine exposed at the cell surface of apoptotic cells.  In addition, HAVCR1 is expressed in T-, B-, and dendritic cells and is involved in the modulation of allergic, asthmatic, and autoimmune responses. Furthermore, HAVCR1 is also expressed on regulatory T-cells and B-cells as a PRR to modulate tolerance. HAVCR1 has been implicated in cell entry of enveloped viruses by apoptotic mimicry via interaction with envelope phospholipids. Some data indicated that the phospholipid binding function and other determinant(s) in the IgV domain of human HAVCR1 enhance HCV infection. Knockdown of HAVCR1 expression reduces HCV entry. Furthermore, some data indicate that HAVCR1 functions early during cell-culture derived J6/JFH1 HCV particles (HCVcc) infection and suggests that this receptor may act at the initial binding stage of entry. Taken together, the integrity of the HAVCR1 phospholipid binding pocket and the IgV domain is responsible for facilitating HCV entry.

One study has shown that the gene encoding the cell surface molecule hepatitis A virus receptor1/kidney injury molecule 1(HAVCR1/KIM-1) is a susceptibility gene for the clear renal carcinoma (ccRCC) and ectodomain shedding of this molecule may be a predictive biomarker of tumor progression. Some results suggest that HAVCR1/KIM-1 upregulation in tumors might represent a novel mechanism to activate tumor growth and angiogenesis, and that pSTAT-3 S727 is an independent prognostic factor for ccRCC.

The T-cell immunoglobulin and mucin domain 4 gene (TIMD4) and the HAVCR1 gene are located on chromosome 5q23 and are members of the T-cell immunoglobulin domain and mucin domain gene family that plays a critical role in regulating immune responses. Some researches proved that the TIMD4-HAVCR1 variants may be the genetic risk factors for coronary heart disease (CHD) and ischemic stroke (IS). TIMD4 is exclusively expressed on antigen-presenting cells, where it mediates phagocytosis of apoptotic cells and plays an important role in maintaining tolerance. In contrast, HAVCR1, an important susceptibility gene for asthma and allergy, is preferentially expressed on T-helper 2 (Th2) cells and functions as a potent costimulatory molecule for T-cell activation. Blockade of TIMD4 and HAVCR1 enhanced the risk of atherosclerosis in low-density lipoprotein (LDL) receptor-deficient mice.

References:

  1. Zhang Q H, et al. Association between the TIMD4-HAVCR1 variants and serum lipid levels, coronary heart disease and ischemic stroke risk and atorvastatin lipid-lowering efficacy. Bioscience Reports, 2018, 38(1).
  2. Kachko A, et al. Determinants in the IgV Domain of human HAVCR1 (TIM-1) are required to enhance Hepatitis C Virus Entry. Journal of Virology, 2018, 92(6):JVI.01742-17.
  3. Cuadros T, et al. HAVCR/KIM-1 activates the IL-6/STAT-3 pathway in clear cell renal cell carcinoma and determines tumor progression and patient outcome. Cancer Research, 2014, 74(5):1416-28.
  4. Das A, et al. TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions. Mbio, 2017, 8(5):558.

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