MHC class I polypeptide–related sequence A explained

MHC class I polypeptide–related sequence A (MICA) is a highly polymorphic cell surface glycoprotein encoded by the MICA gene located within MHC locus.[1] MICA is related to MHC class I and it has similar domain structure, however, it is not associated with β2-microglobulin nor binds peptides as conventional MHC class I molecules do.[2] MICA rather functions as a stress-induced ligand (as a danger signal) for integral membrane protein receptor NKG2D ("natural-killer group 2, member D"). MICA is broadly recognized by NK cells, γδ T cells, and CD8+ αβ T cells which carry NKG2D receptor on their cell surface and which are activated via this interaction.[3]

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.[4] 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.[5]

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 (HCMV), human adenovirus 5, M. tuberculosis, diarrheagenic E.coli, or human papillomavirus (HPV).[6]

microRNA-183 downregulates MICA expression after exposure to transforming growth factor beta (TGFβ).[7]

In normal tissue, MICA is expressed mainly intracellularly with just a small fraction appearing on the surface of some epithelial cells.[8] There is no expression of MICA in the cells of the central nervous system (CNS).

Function

MICA plays the role of stress-induced self-antigen and serves as a ligand for the KLRK1/NKG2D killer activation receptor.[9] 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.[10] High levels of MICA in the serum of tumor patients are positively related to tumor size and poor prognosis.[11]

Variations in the MICA gene are also associated with susceptibility to psoriasis 1 and psoriatic arthritis and MICA-specific antibodies or its shedding are involved in the monoclonal gammopathy of undetermined significance´s (MGUS) progression to multiple myeloma.

See also

Further reading

Notes and References

  1. Bahram S, Bresnahan M, Geraghty DE, Spies T . A second lineage of mammalian major histocompatibility complex class I genes . Proceedings of the National Academy of Sciences of the United States of America . 91 . 14 . 6259–63 . July 1994 . 8022771 . 44180 . 10.1073/pnas.91.14.6259 . 1994PNAS...91.6259B . free .
  2. Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T . Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium . Proceedings of the National Academy of Sciences of the United States of America . 93 . 22 . 12445–50 . October 1996 . 8901601 . 38011 . 10.1073/pnas.93.22.12445 . 1996PNAS...9312445G . free .
  3. Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T . Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA . Science . 285 . 5428 . 727–9 . July 1999 . 10426993 . 10.1126/science.285.5428.727 .
  4. Zou Y, Stastny P . Alternatively spliced forms of MICA and MICB lacking exon 3 in a human cell line and evidence of presence of similar RNA in human peripheral blood mononuclear cells . Immunogenetics . 54 . 9 . 671–4 . December 2002 . 12466900 . 10.1016/s0198-8859(02)00518-9 .
  5. Mistry AR, O'Callaghan CA . Regulation of ligands for the activating receptor NKG2D . Immunology . 121 . 4 . 439–47 . August 2007 . 17614877 . 2265965 . 10.1111/j.1365-2567.2007.02652.x.
  6. Ramachandran D, Schürmann P, Mao Q, Wang Y, Bretschneider LM, Speith LM, Hülse F, Enßen J, Bousset K, Jentschke M, Böhmer G, Strauß HG, Hirchenhain C, Schmidmayr M, Tarbiat J, Runnebaum I, Dürst M, Hein A, Koch M, Ruebner M, Ekici A, Beckmann MW, Fasching PA, Luyten A, Petry KU, Hillemanns P, Dörk T . Association of genomic variants at the Human Leukocyte Antigen locus with cervical cancer risk, HPV status, and gene expression levels. International Journal of Cancer . 2020. 147. 9. 2458–2468. 32580243 . 10.1002/ijc.33171. free .
  7. Trinh. Thu Le. Kandell. Wendy M.. Donatelli. Sarah S.. Tu. Nhan. Tejera. Melba M.. Gilvary. Danielle L.. Eksioglu. Erika A.. Burnette. Alexis. Adams. William A.. 2019-01-17. Immune evasion by TGFβ-induced miR-183 repression of MICA/B expression in human lung tumor cells. OncoImmunology. 8. 4. e1557372. 10.1080/2162402x.2018.1557372. 30906652. 6422376. 2162-402X. free.
  8. Ghadially H, Brown L, Lloyd C, Lewis L, Lewis A, Dillon J, Sainson R, Jovanovic J, Tigue NJ, Bannister D, Bamber L, Valge-Archer V, Wilkinson RW . MHC class I chain-related protein A and B (MICA and MICB) are predominantly expressed intracellularly in tumour and normal tissue . British Journal of Cancer . 116 . 9 . 1208–1217 . April 2017 . 28334733 . 5418453 . 10.1038/bjc.2017.79.
  9. Song P, Zhao Q, Zou M . Targeting senescent cells to attenuate cardiovascular disease progression . . 60 . 101072 . 2020 . 10.1016/j.arr.2020.101072 . 7263313 . 32298812.
  10. Ferrari de Andrade L, Tay RE, Pan D, Luoma AM, Ito Y, Badrinath S, Tsoucas D, Franz B, May KF, Harvey CJ, Kobold S, Pyrdol JW, Yoon C, Yuan GC, Hodi FS, Dranoff G, Wucherpfennig KW . Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity . Science . 359 . 6383 . 1537–1542 . March 2018 . 29599246 . 10.1126/science.aao0505. 6626532 . 2018Sci...359.1537F . free .
  11. Li JJ, Pan K, Gu MF, Chen MS, Zhao JJ, Wang H, Liang XT, Sun JC, Xia JC . Prognostic value of soluble MICA levels in the serum of patients with advanced hepatocellular carcinoma . Chinese Journal of Cancer . 32 . 3 . 141–8 . March 2013 . 22704489 . 3845598 . 10.5732/cjc.012.10025 .

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