MHC class I polypeptide–related sequence A (MICA) is a highly polymorphic 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 ...

encoded by the ''MICA''

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 ...

located within MHC locus. MICA is related to

MHC class I MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on ...

and it has similar domain structure, however, it is not associated with

β2-microglobulin β2 microglobulin (B2M) is a component of MHC class I molecules. MHC class I molecules have α1, α2, and α3 proteins which are present on all nucleated cells (excluding red blood cells). In humans, the β2 microglobulin protein is encoded by t ...

nor binds peptides as conventional MHC class I molecules do. MICA rather functions as a stress-induced ligand (as a danger signal) for integral membrane protein receptor

NKG2D NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors. NKG2D is encoded by ''KLRK1'' (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated ...

("''natural-killer group 2, member D''"). MICA is broadly recognized by

NK cells Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cell ...

γδ T cells Gamma delta T cells (γδ T cells) are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ (alpha beta) T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, ...

, and CD8⁺ αβ

T cells 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 ...

which carry NKG2D receptor on their cell surface and which are activated ''via'' this interaction.

Structure

The MICA gene is highly polymorphic in humans with more than 50 defined alleles. It is located on chromosome 6 and the protein is expressed in two isoforms formed by alternative splicing: MICA1 and MICA2 which is lacking exon 3. MICA contains external α1α2α3 domain, transmembrane segment and C-terminal cytoplasmic tail. It binds in a form of monomer to a KLRK1/NKG2D homodimer. There are no orthologs of the MICA in mice species.

Expression

Expression of MICA can be upregulated by heat shock or by exposure of the cells to DNA damaging conditions (for example ionizing radiation, chromatin-modifying interventions and inhibitors of DNA replication). The expression can be as well affected by some infectious agents such as

human cytomegalovirus Human cytomegalovirus (HCMV), also called human herpesvirus 5 (HHV-5), is a species of virus in the genus ''Cytomegalovirus'', which in turn is a member of the viral family known as ''Herpesviridae'' or herpesviruses. It is also commonly call ...

(HCMV), human

adenovirus Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from t ...

5, ''

M. tuberculosis ''Mycobacterium tuberculosis'' (M. tb), also known as Koch's bacillus, is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' ha ...

'', diarrheagenic ''

E.coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escherichia'' that is commonly foun ...

'', or

human papillomavirus Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and r ...

(HPV).

microRNA Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcr ...

-183 downregulates MICA expression after exposure to

transforming growth factor beta Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...

(TGFβ). In normal tissue, MICA is expressed mainly intracellularly with just a small fraction appearing on the surface of some epithelial cells. There is no expression of MICA in the cells of the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

(CNS).

Function

MICA plays the role of stress-induced self-antigen and serves as a

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

for the KLRK1/NKG2D

killer activation receptor Killer Activation Receptors (KARs) are receptors expressed on the plasma membrane (cell membrane) of Natural Killer cells (NK cells). KARs work together with Killer Inhibitory Receptors (abbreviated as KIRs in the text), which inactivate KARs in o ...

. Engagement of NKG2D-MICA results in activation of effector cytolytic responses of T cells and NK cells against epithelial tumor cells (or other stressed cells) expressing MICA on their surface. As a defense mechanism, tumor cells are able to avoid recognition of MICA by the immune system through proteolytic shedding of the surface expressed protein by the cooperation of disulfide isomerase (ERp5) and ADAM (a disintegrin and metalloproteinase) and MMP (matrix metalloproteinase) proteases targeting membrane-proximal α3 domain. High levels of MICA in the serum of tumor patients are positively related to tumor size and poor prognosis. Variations in the MICA gene are also associated with susceptibility to psoriasis 1 and

psoriatic arthritis Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that may occur in some people affected by the autoimmune disease psoriasis. The classic features of psoriatic arthritis include dactylitis (sausage-like swelling of the fingers ...

and MICA-specific antibodies or its shedding are involved in the

monoclonal gammopathy of undetermined significance Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell dyscrasia in which plasma cells or other types of antibody-producing cells secrete a myeloma protein, i.e. an abnormal antibody, into the blood; this abnormal protein is u ...

´s (MGUS) progression to

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...

Structure

Expression

Function

See also

References

Further reading