Common gamma chain explained

The common gamma chain (γ_c) (or CD132), also known as interleukin-2 receptor subunit gamma or IL-2RG, is a cytokine receptor sub-unit that is common to the receptor complexes for at least six different interleukin receptors: IL-2, IL-4,^[1] IL-7,^[2] IL-9, IL-15^[3] and interleukin-21 receptor. The γ_c glycoprotein is a member of the type I cytokine receptor family expressed on most lymphocyte (white blood cell) populations, and its gene is found on the X-chromosome of mammals.

This protein is located on the surface of immature blood-forming cells in bone marrow. One end of the protein resides outside the cell where it binds to cytokines and the other end of the protein resides in the interior of the cell where it transmits signals to the cell's nucleus. The common gamma chain partners with other proteins to direct blood-forming cells to form lymphocytes (a type of white blood cell). The receptor also directs the growth and maturation of lymphocyte subtypes: T cells, B cells, and natural killer cells. These cells kill viruses, make antibodies, and help regulate the entire immune system.

Gene

Cytokine receptor common subunit gamma also known as interleukin-2 receptor subunit gamma or IL-2RG is a protein that in humans is encoded by the IL2RG gene.^[4] The human IL2RG gene is located on the long (q) arm of the X chromosome at position 13.1, from base pair 70,110,279 to base pair 70,114,423.

Structure

The γ_c chain is an integral membrane protein that contains extracellular, transmembrane, and intracellular domains.

Function

Lymphocytes expressing the common gamma chain can form functional receptors for these cytokine proteins, which transmit signals from one cell to another and direct programs of cellular differentiation.

Ligands

The γ_c chain partners with other ligand-specific receptors to direct lymphocytes to respond to cytokines including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.^[5]

Signalling

IL2RG has been shown to interact with Janus kinase 3.^{[6] [7]}

Clinical significance

X-linked severe combined immunodeficiency

X-linked severe combined immunodeficiency is caused by mutations in the IL2RG gene. More than 200 different mutations in the IL2RG gene have been identified in people with X-linked severe combined immunodeficiency (SCID).^[8] Most of these mutations involve changes in one or a few nucleotides (DNA building blocks) in the gene. These changes lead to the production of a nonfunctional version of the common gamma chain protein or no production of protein.^[9] Without the common gamma chain, important chemical signals are not relayed to the nucleus and lymphocytes cannot develop normally. A lack of functional mature lymphocytes disrupts the immune system's ability to protect the body from infection. Affected people have no functional immunity and can die within months after birth without successful bone marrow transplantation or alternatively, isolation from exposure to pathogens. Without important developmental signals from IL-7 and IL-15, T-cell and NK cell populations respectively fail to develop.

Experiments in animal models have shown X-SCID to occur similarly in dogs, but not in mice.^[10]

Schizophrenia

Alterations in the immune response are involved in pathogenesis of many neuropsychiatric disorders including schizophrenia. Distinct gene variants of a number of pro-inflammatory and chemotactic cytokines together with their receptors associate with this disorder. IL2RG represents an important signaling component of many interleukin receptors and so far, no data on the functional state of this receptor in schizophrenia have been reported. Over-expression of the IL2RG gene may be implicated in altered immune response in schizophrenia and contribute to the pathogenesis of this disorder.^[11]

Further reading

• Buckley RH . Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution . Annu Rev Immunol . 2004 . 625–55 . 22 . 15032591 . 10.1146/annurev.immunol.22.012703.104614.
• Kalman L, Lindegren ML, Kobrynski L, Vogt R, Hannon H, Howard JT, Buckley R . Mutations in genes required for T-cell development: IL7R, CD45, IL2RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HuGE review . Genet Med . 2004 . 16–26 . 6 . 1 . 14726805 . 10.1097/01.GIM.0000105752.80592.A3. free .
• Ellery JM, Nicholls PJ . Alternate signalling pathways from the interleukin-2 receptor . Cytokine Growth Factor Rev. . 13 . 1 . 27–40 . 2002 . 11750878 . 10.1016/S1359-6101(01)00023-5 .
• Takeshita T, Asao H, Ohtani K, Ishii N, Kumaki S, Tanaka N, Munakata H, Nakamura M, Sugamura K . Cloning of the gamma chain of the human IL-2 receptor . Science . 257 . 5068 . 379–82 . July 1992 . 1631559 . 10.1126/science.1631559 . 1992Sci...257..379T .
• Burton J, Goldman CK, Rao P, Moos M, Waldmann TA . Association of intercellular adhesion molecule 1 with the multichain high-affinity interleukin 2 receptor . Proc. Natl. Acad. Sci. U.S.A. . 87 . 18 . 7329–33 . September 1990 . 1976256 . 54737 . 10.1073/pnas.87.18.7329 . 1990PNAS...87.7329B . free .
• Oyaizu N, Chirmule N, Kalyanaraman VS, Hall WW, Pahwa R, Shuster M, Pahwa S . Human immunodeficiency virus type 1 envelope glycoprotein gp120 produces immune defects in CD4+ T lymphocytes by inhibiting interleukin 2 mRNA . Proc. Natl. Acad. Sci. U.S.A. . 87 . 6 . 2379–83 . March 1990 . 2315327 . 53690 . 10.1073/pnas.87.6.2379 . 1990PNAS...87.2379O . free .
• Kornfeld H, Cruikshank WW, Pyle SW, Berman JS, Center DM . Lymphocyte activation by HIV-1 envelope glycoprotein . Nature . 335 . 6189 . 445–8 . September 1988 . 2843775 . 10.1038/335445a0 . 1988Natur.335..445K . 4326650 .
• Bamborough P, Hedgecock CJ, Richards WG . The interleukin-2 and interleukin-4 receptors studied by molecular modelling . Structure . 2 . 9 . 839–51 . 1995 . 7529123 . 10.1016/S0969-2126(94)00085-9 .
• Clark PA, Lester T, Genet S, Jones AM, Hendriks R, Levinsky RJ, Kinnon C . Screening for mutations causing X-linked severe combined immunodeficiency in the IL-2R gamma chain gene by single-strand conformation polymorphism analysis . Hum. Genet. . 96 . 4 . 427–32 . October 1995 . 7557965 . 10.1007/BF00191801 . 29039832 .
• Pepper AE, Buckley RH, Small TN, Puck JM . Two mutational hotspots in the interleukin-2 receptor gamma chain gene causing human X-linked severe combined immunodeficiency . Am. J. Hum. Genet. . 57 . 3 . 564–71 . September 1995 . 7668284 . 1801277 .
• Ohbo K, Takasawa N, Ishii N, Tanaka N, Nakamura M, Sugamura K . Functional analysis of the human interleukin 2 receptor gamma chain gene promoter . J. Biol. Chem. . 270 . 13 . 7479–86 . March 1995 . 7706294 . 10.1074/jbc.270.13.7479 . free .
• Puck JM, Pepper AE, Bédard PM, Laframboise R . Female germ line mosaicism as the origin of a unique IL-2 receptor gamma-chain mutation causing X-linked severe combined immunodeficiency . J. Clin. Invest. . 95 . 2 . 895–9 . February 1995 . 7860773 . 295580 . 10.1172/JCI117740 .
• DiSanto JP, Rieux-Laucat F, Dautry-Varsat A, Fischer A, de Saint Basile G . Defective human interleukin 2 receptor gamma chain in an atypical X chromosome-linked severe combined immunodeficiency with peripheral T cells . Proc. Natl. Acad. Sci. U.S.A. . 91 . 20 . 9466–70 . September 1994 . 7937790 . 44833 . 10.1073/pnas.91.20.9466 . 1994PNAS...91.9466D . free .
• Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O . Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID . Science . 266 . 5187 . 1042–5 . November 1994 . 7973658 . 10.1126/science.7973658 . 1994Sci...266.1042R .
• Ishii N, Asao H, Kimura Y, Takeshita T, Nakamura M, Tsuchiya S, Konno T, Maeda M, Uchiyama T, Sugamura K . Impairment of ligand binding and growth signaling of mutant IL-2 receptor gamma-chains in patients with X-linked severe combined immunodeficiency . J. Immunol. . 153 . 3 . 1310–7 . August 1994 . 10.4049/jimmunol.153.3.1310 . 8027558 . 24092176 .
• Johnson K, Choi Y, Wu Z, Ciardelli T, Granzow R, Whalen C, Sana T, Pardee G, Smith K, Creasey A . Soluble IL-2 receptor beta and gamma subunits: ligand binding and cooperativity . Eur. Cytokine Netw. . 5 . 1 . 23–34 . 1994 . 8049354 .
• Markiewicz S, Subtil A, Dautry-Varsat A, Fischer A, de Saint Basile G . Detection of three nonsense mutations and one missense mutation in the interleukin-2 receptor gamma chain gene in SCIDX1 that differently affect the mRNA processing . Genomics . 21 . 1 . 291–3 . May 1994 . 8088810 . 10.1006/geno.1994.1265 .
• Kondo M, Takeshita T, Ishii N, Nakamura M, Watanabe S, Arai K, Sugamura K . Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4 . Science . 262 . 5141 . 1874–7 . December 1993 . 8266076 . 10.1126/science.8266076 . 1993Sci...262.1874K .

Notes and References

1. Russell SM, Keegan AD, Harada N, Nakamura Y, Noguchi M, Leland P, Friedmann MC, Miyajima A, Puri RK, Paul WE . Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor . Science . 262 . 5141 . 1880–3 . December 1993 . 8266078 . 10.1126/science.8266078 . 1993Sci...262.1880R .
2. Noguchi M, Nakamura Y, Russell SM, Ziegler SF, Tsang M, Cao X, Leonard WJ . Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor . Science . 262 . 5141 . 1877–80 . December 1993 . 8266077 . 10.1126/science.8266077 . 1993Sci...262.1877N .
3. Giri JG, Kumaki S, Ahdieh M, Friend DJ, Loomis A, Shanebeck K, DuBose R, Cosman D, Park LS, Anderson DM . Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor . EMBO J. . 14 . 15 . 3654–63 . August 1995 . 7641685 . 394440 . 10.1002/j.1460-2075.1995.tb00035.x.
4. Takeshita T, Asao H, Ohtani K, Ishii N, Kumaki S, Tanaka N, Munakata H, Nakamura M, Sugamura K . Cloning of the gamma chain of the human IL-2 receptor . Science . 257 . 5068 . 379–82 . July 1992 . 1631559 . 10.1126/science.1631559. 1992Sci...257..379T .
5. Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K . Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex . J. Immunol. . 167 . 1 . 1–5 . July 2001 . 11418623 . 10.4049/jimmunol.167.1.1. free .
6. Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu ZJ, Oishi I, Silvennoinen O, Witthuhn BA, Ihle JN . Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits . Science . 266 . 5187 . 1045–7 . November 1994 . 7973659 . 10.1126/science.7973659. 1994Sci...266.1045M .
7. Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O . Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID . Science . 266 . 5187 . 1042–5 . November 1994 . 7973658 . 10.1126/science.7973658 . 1994Sci...266.1042R .
8. Book: Vihinen M, Arredondo-Vega FX, Casanova JL, Etzioni A, Giliani S, Hammarström L, Hershfield MS, Heyworth PG, Hsu AP, Lähdesmäki A, Lappalainen I, Notarangelo LD, Puck JM, Reith W, Roos D, Schumacher RF, Schwarz K, Vezzoni P, Villa A, Väliaho J, Smith CI . 4 Primary immunodeficiency mutation databases . Advances in Genetics . 43 . 103–88 . 2001 . 11037300 . 10.1016/s0065-2660(01)43005-7 . Advances in Genetics --> . 9780120176434 .
9. Schmalstieg FC, Leonard WJ, Noguchi M, Berg M, Rudloff HE, Denney RM, Dave SK, Brooks EG, Goldman AS . Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency . J. Clin. Invest. . 95 . 3 . 1169–73 . March 1995 . 7883965 . 441454 . 10.1172/JCI117765 .
10. Henthorn PS, Somberg RL, Fimiani VM, Puck JM, Patterson DF, Felsburg PJ . IL-2R gamma gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease . Genomics . 23 . 1 . 69–74 . September 1994 . 7829104 . 10.1006/geno.1994.1460 . free .
11. Ghazaryan H, Petrek M, Boyajyan A . Chronic schizophrenia is associated with over-expression of the interleukin-2 receptor gamma gene . Psychiatry Res . 217 . 3 . 158–62 . 2014 . 24713359 . 10.1016/j.psychres.2014.03.020 . 44296846 .