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词条 MHC class I polypeptide-related sequence A
释义

  1. Structure

  2. Expression

  3. Function

  4. See also

  5. References

  6. Further reading


{{Infobox_gene}}

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.[5]

There are no orthologs of the MICA in mice species.[6]

Expression

Expression of MICA can be upregulated by heat shock[2] 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 or diarrheagenic E.coli.[5]

In the negative regulation of MICA expression, microRNA-183 plays an important. It downregulates its 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). [5]

Function

MICA plays the role of stress-induced self-antigen and serves as a ligand for the KLRK1/NKG2D receptor. Engagement of NKG2D-MICA results in activation of effector cytolytic responses of T cells and NK cells against epithelial tumour cells (or other stressed cells) expressing MICA on their surface.[3]

As a defence mechanism, tumour cells are able to avoid the recognition of MICA by 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.[9] High levels of MICA in the serum of tumour patients are possitively related to tumour size and poor prognosis.[10]

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.[5]

See also

  • MHC class I
  • Major histocompatibility complex
  • MHC class I polypeptide-related sequence B

References

1. ^{{cite journal | vauthors = Bahram S, Bresnahan M, Geraghty DE, Spies T | title = A second lineage of mammalian major histocompatibility complex class I genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 14 | pages = 6259–63 | date = July 1994 | pmid = 8022771 | pmc = 44180 | doi = 10.1073/pnas.91.14.6259 }}
2. ^1 {{cite journal | vauthors = Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T | title = Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 22 | pages = 12445–50 | date = October 1996 | pmid = 8901601 | pmc = 38011 | doi = 10.1073/pnas.93.22.12445 }}
3. ^1 {{cite journal | vauthors = Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T | title = Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA | journal = Science | volume = 285 | issue = 5428 | pages = 727–9 | date = July 1999 | pmid = 10426993 | doi = 10.1126/science.285.5428.727 }}
4. ^{{cite journal | vauthors = Zou Y, Stastny P | title = 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 | journal = Immunogenetics | volume = 54 | issue = 9 | pages = 671–4 | date = December 2002 | pmid = 12466900 | doi = 10.1016/s0198-8859(02)00518-9 }}
5. ^1 2 3 {{UniProt Full|Q29983|MICA - MHC class I polypeptide-related sequence A precursor - Homo sapiens (Human) - MICA gene & protein}}
6. ^{{cite journal | vauthors = Mistry AR, O'Callaghan CA | title = Regulation of ligands for the activating receptor NKG2D | journal = Immunology | volume = 121 | issue = 4 | pages = 439–47 | date = August 2007 | pmid = 17614877 | pmc = 2265965 | doi = 10.1111/j.1365-2567.2007.02652.x}}
7. ^{{Cite journal|last=Trinh|first=Thu Le|last2=Kandell|first2=Wendy M.|last3=Donatelli|first3=Sarah S.|last4=Tu|first4=Nhan|last5=Tejera|first5=Melba M.|last6=Gilvary|first6=Danielle L.|last7=Eksioglu|first7=Erika A.|last8=Burnette|first8=Alexis|last9=Adams|first9=William A.|date=2019-01-17|title=Immune evasion by TGFβ-induced miR-183 repression of MICA/B expression in human lung tumor cells|journal=OncoImmunology|pages=1–11|doi=10.1080/2162402x.2018.1557372|issn=2162-402X}}
8. ^{{cite journal | vauthors = 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 | title = MHC class I chain-related protein A and B (MICA and MICB) are predominantly expressed intracellularly in tumour and normal tissue | journal = British Journal of Cancer | volume = 116 | issue = 9 | pages = 1208–1217 | date = April 2017 | pmid = 28334733 | pmc = 5418453 | doi = 10.1038/bjc.2017.79}}
9. ^{{cite journal | vauthors = 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 | title = Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity | journal = Science | volume = 359 | issue = 6383 | pages = 1537–1542 | date = March 2018 | pmid = 29599246 | doi = 10.1126/science.aao0505}}
10. ^{{cite journal | vauthors = Li JJ, Pan K, Gu MF, Chen MS, Zhao JJ, Wang H, Liang XT, Sun JC, Xia JC | title = Prognostic value of soluble MICA levels in the serum of patients with advanced hepatocellular carcinoma | journal = Chinese Journal of Cancer | volume = 32 | issue = 3 | pages = 141–8 | date = March 2013 | pmid = 22704489 | pmc = 3845598 | doi = 10.5732/cjc.012.10025 }}

Further reading

{{refbegin | 2}}
  • {{cite journal | vauthors = Klein J, O'hUigin C | title = The conundrum of nonclassical major histocompatibility complex genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 14 | pages = 6251–2 | date = July 1994 | pmid = 8022769 | pmc = 44177 | doi = 10.1073/pnas.91.14.6251 }}
  • {{cite journal | vauthors = Bahram S, Spies T | title = The MIC gene family | journal = Research in Immunology | volume = 147 | issue = 5 | pages = 328–33 | date = June 1996 | pmid = 8876061 | doi = 10.1016/0923-2494(96)89646-5 }}
  • {{cite journal | vauthors = Blumberg RS | title = Current concepts in mucosal immunity. II. One size fits all: nonclassical MHC molecules fulfill multiple roles in epithelial cell function | journal = The American Journal of Physiology | volume = 274 | issue = 2 Pt 1 | pages = G227–31 | date = February 1998 | pmid = 9486173 | doi = }}
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