Hepatitis A virus cellular receptor 1 (HAVcr-1) also known as T-cell immunoglobulin and mucin domain 1 (TIM-1) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''HAVCR1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. 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. 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 White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cell (biology), cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood c ...

activity especially regarding the host response to

viral infection A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells. Examples include the common cold, gastroenteritis, COVID-19, t ...

. TIM-1 is also involved in

allergic response An allergic response is a hypersensitive immune reaction to a substance that normally is harmless or would not cause an immune response in everyone. An allergic response may cause harmful symptoms such as itching or inflammation or tissue inju ...

asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...

, and transplant tolerance. The TIM gene family was first cloned from the mouse model of asthma in 2001. Subsequently, it was demonstrated that members of the TIM gene family including TIM-1 participate in host

immune response An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellula ...

. 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

glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...

s, which include an N-terminal

immunoglobulin An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

(Ig)-like domain, a

mucin Mucins () are a family of high molecular weight, heavily glycosylated proteins ( glycoconjugates) produced by epithelial tissues in most animals. Mucins' key characteristic is their ability to form gels; therefore they are a key component in ...

domain with distinct length, a single

transmembrane domain A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in ...

, and a

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

short

cytoplasmic The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell and ...

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 T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...

activation. TIM-3 is preferentially expressed on Th1 and Tc1 cells and function as an inhibitory molecule, which mediated apoptosis of Th1 and Tc1 cells. TIM-4 is preferentially expressed on

antigen-presenting cell An antigen-presenting cell (APC) or accessory cell is a Cell (biology), cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize the ...

s, modulating the

phagocytosis Phagocytosis () is the process by which a cell (biology), cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs ph ...

apoptotic Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes ( morphology) and death. These ...

cells by interacting with

phosphatidylserine Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is a phospholipid and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via a ...

(PS) exposed on apoptotic cell surface.

Role in viral infection

TIM genes are also involved in host-virus interaction. As receptors for phosphatidylserine, TIM proteins bind many families of viruses ilovirus, flavivirus, New World arenavirus and alphavirusthat 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.

Hepatitis A

TIM-1 has been identified as an attachment factor for exosome-packaged

hepatitis A virus Hepatitis A is an infectious liver disease caused by Hepatitis A virus (HAV); it is a type of viral hepatitis. Many cases have few or no symptoms, especially in the young. The time between infection and symptoms, in those who develop them, is ...

(HAV). Infectious HAV-containing exosomes are internalized by HAVCR1, but true entry into the cytosol is achieved through fusion with

NPC1 Niemann-Pick disease, type C1 (NPC1) is a membrane protein that mediates intracellular cholesterol trafficking in mammals. In humans the protein is encoded by the ''NPC1'' gene (chromosome location 18q11). Function ''NPC1'' was identified as ...

. It has also been shown that non-exosomal HAV (encapsidated) infection occurs independent of HAVCR1 expression. By using an expression cloning library,

IgA IGA or IgA may refer to: Businesses and organizations * IGA (supermarkets) (initially Independent Grocers Alliance), a name used by many independent supermarkets throughout the world ** IGA (Australian supermarket group), the local Australian v ...

has been demonstrated as a specific ligand of TIM-1. The association of TIM-1 and

was able to enhance the virus-receptor interaction.

Ebola

Recently, TIM-1 has been shown to be a receptor or cofactor for

Ebola virus ''Orthoebolavirus zairense'' or Zaire ebolavirus, more commonly known as Ebola virus (; EBOV), is one of six known species within the genus ''Ebolavirus''. Four of the six known ebolaviruses, including EBOV, cause a severe and often fatal vira ...

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. 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 Dengue virus (DENV) is the cause of dengue fever. It is a mosquito-borne, single positive-stranded RNA virus of the family ''Flaviviridae''; genus '' Flavivirus''. Four serotypes of the virus have been found, and a reported fifth has yet to be ...

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. 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.

Structure and function

Role in viral infection

Hepatitis A

Ebola

Dengue

References

Further reading