View source for Common gamma chain

{{Short description|Protein-coding gene in humans}}
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{{Infobox_gene}}
The '''common gamma chain''' (γ<sub>c</sub>) (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]]: [[interleukin-2 receptor|IL-2]], [[interleukin-4 receptor|IL-4]],<ref name="pmid8266078">{{cite journal | vauthors = Russell SM, Keegan AD, Harada N, Nakamura Y, Noguchi M, Leland P, Friedmann MC, Miyajima A, Puri RK, Paul WE | title = Interleukin-2 receptor gamma chain: a functional component of the interleukin-4 receptor | journal = Science | volume = 262 | issue = 5141 | pages = 1880–3 |date=December 1993 | pmid = 8266078 | doi = 10.1126/science.8266078 | bibcode = 1993Sci...262.1880R | url = https://zenodo.org/record/1231251 }}</ref> [[interleukin-7 receptor|IL-7]],<ref name="pmid8266077">{{cite journal | vauthors = Noguchi M, Nakamura Y, Russell SM, Ziegler SF, Tsang M, Cao X, Leonard WJ | title = Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor | journal = Science | volume = 262 | issue = 5141 | pages = 1877–80 |date=December 1993 | pmid = 8266077 | doi = 10.1126/science.8266077 | bibcode = 1993Sci...262.1877N | url = https://zenodo.org/record/1231251 }}</ref> [[interleukin-9 receptor|IL-9]], [[interleukin-15 receptor|IL-15]]<ref name="pmid7641685">{{cite journal | vauthors = Giri JG, Kumaki S, Ahdieh M, Friend DJ, Loomis A, Shanebeck K, DuBose R, Cosman D, Park LS, Anderson DM | title = Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor | journal = EMBO J. | volume = 14 | issue = 15 | pages = 3654–63 |date=August 1995 | pmid = 7641685 | pmc = 394440 | doi = 10.1002/j.1460-2075.1995.tb00035.x}}</ref> and [[interleukin-21 receptor]]. The γ<sub>c</sub> [[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 [[cytokine]]s 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 [[lymphocyte]]s (a type of white blood cell). The receptor also directs the growth and maturation of lymphocyte subtypes: [[T cell]]s, [[B cell]]s, [[Innate lymphoid cell|innate lymphoid cells]], and [[natural killer cell]]s. 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]].<ref name="pmid1631559">{{cite journal | vauthors = Takeshita T, Asao H, Ohtani K, Ishii N, Kumaki S, Tanaka N, Munakata H, Nakamura M, Sugamura K | title = Cloning of the gamma chain of the human IL-2 receptor | journal = Science | volume = 257 | issue = 5068 | pages = 379–82 |date=July 1992 | pmid = 1631559 | doi = 10.1126/science.1631559| bibcode = 1992Sci...257..379T }}</ref> 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.

[[File:IL-7receptor and signaling.jpg|thumb|180px|left|'''IL-7 receptor and signaling''', common γ chain (blue) and IL-7 receptor-α (green)]]

==Structure==
The γ<sub>c</sub> 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 [[cell signaling|signals]] from one cell to another and direct programs of [[cellular differentiation]].

=== Ligands ===
The γ<sub>c</sub> chain partners with other [[ligand]]-specific receptors to direct lymphocytes to respond to [[cytokine]]s including [[interleukin 2|IL-2]], [[interleukin 4|IL-4]], [[interleukin 7|IL-7]], [[interleukin 9|IL-9]], [[interleukin 15|IL-15]] and [[interleukin 21|IL-21]].<ref name="pmid11418623">{{cite journal | vauthors = Asao H, Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K | title = Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex | journal = J. Immunol. | volume = 167 | issue = 1 | pages = 1–5 |date=July 2001 | pmid = 11418623 | doi = 10.4049/jimmunol.167.1.1| doi-access = free }}</ref>

=== Signaling ===

IL2RG has been shown to [[Protein-protein interaction|interact]] with [[Janus kinase 3]].<ref name="pmid7973659">{{cite journal | vauthors = Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu ZJ, Oishi I, Silvennoinen O, Witthuhn BA, Ihle JN | title = Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits | journal = Science | volume = 266 | issue = 5187 | pages = 1045–7 |date=November 1994 | pmid = 7973659 | doi = 10.1126/science.7973659| bibcode = 1994Sci...266.1045M }}</ref><ref name="pmid7973658">{{cite journal | vauthors = Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O | title = Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID | journal = Science | volume = 266 | issue = 5187 | pages = 1042–5 |date=November 1994 | pmid = 7973658 | doi = 10.1126/science.7973658 | bibcode = 1994Sci...266.1042R | url = https://zenodo.org/record/1231239 }}</ref>

IL2RG plays a critical role in lymphocyte signal transduction in response to [[Interleukin 4|IL-4]], [[Interleukin 7|IL-7]], [[Interleukin 9|IL-9]], [[Interleukin 21|IL-21]], [[Interleukin 15 |IL-15]], and [[Interleukin 2|IL-2]]. Once either [[Interleukin-4 receptor|IL4-Rα]], [[Interleukin-7 receptor|IL-7Rα]], [[Interleukin-9 receptor|IL-9Rα]], [[Interleukin-21 receptor|IL-21Rα]], [[IL-2 receptor|IL-2R]] or [[Interleukin-15 receptor|IL-15R]] has bound to their respective ligands, IL2RG is quickly recruited and forms a [[Protein dimer|heterodimer]] with the cytoplasmic tail of the opposing receptor. After the heterodimer has formed, IL2RG then activates [[Janus kinase 3|JAK3]], and the opposing receptor activates [[Janus kinase 1|JAK1]]. JAK1 and JAK3 then [[Protein phosphorylation|phosphorylate]] both IL2RG and the opposing receptor's cytoplasmic tail. This phosphorylation allows for IL-2RG and its opposing receptor to recruit a [[STAT protein|STAT]] protein. JAK3 and JAK1 subsequently phosphorylate the recruited STAT, allowing the STAT to form a dimer or [[tetramer]] with other phosphorylated STAT proteins. Finally, these dimer or STATs translocate to the nucleus, bind STAT motifs within the nuclear DNA, and induce transcription within specific genes.<ref>{{cite journal | vauthors = Lin JX, Leonard WJ | title = The Common Cytokine Receptor γ Chain Family of Cytokines | journal = Cold Spring Harbor Perspectives in Biology | volume = 10 | issue = 9 | date = September 2018 | pmid = 29038115 | doi = 10.1101/cshperspect.a028449 | pmc = 6120701 }}</ref>

==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).<ref name="pmid11037300">{{Cite book | vauthors = 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 | chapter= 4 Primary immunodeficiency mutation databases |title=Advances in Genetics | volume = 43 | pages = 103–88 | year = 2001 | pmid = 11037300 | doi = 10.1016/s0065-2660(01)43005-7 <!-- | series = Advances in Genetics --> | isbn = 9780120176434 }}</ref> 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 {{Citation needed|date=February 2011}} or no production of protein.<ref name="pmid7883965">{{cite journal | vauthors = Schmalstieg FC, Leonard WJ, Noguchi M, Berg M, Rudloff HE, Denney RM, Dave SK, Brooks EG, Goldman AS | title = Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency | journal = J. Clin. Invest. | volume = 95 | issue = 3 | pages = 1169–73 |date=March 1995 | pmid = 7883965 | pmc = 441454 | doi = 10.1172/JCI117765 }}</ref> 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 transplant]]ation 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.<ref name="pmid7829104">{{cite journal | vauthors = Henthorn PS, Somberg RL, Fimiani VM, Puck JM, Patterson DF, Felsburg PJ | title = IL-2R gamma gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease | journal = Genomics | volume = 23 | issue = 1 | pages = 69–74 |date=September 1994 | pmid = 7829104 | doi = 10.1006/geno.1994.1460 | doi-access = free }}</ref>

=== 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.<ref name="pmid24713359">{{cite journal | vauthors = Ghazaryan H, Petrek M, Boyajyan A | title = Chronic schizophrenia is associated with over-expression of the interleukin-2 receptor gamma gene | journal = Psychiatry Res | volume = 217 | issue = 3 | pages = 158–62 | year = 2014 | pmid = 24713359 | doi = 10.1016/j.psychres.2014.03.020 | s2cid = 44296846 }}</ref>

==References==
{{reflist|35em}}

==Further reading==
{{refbegin|35em}}
* {{cite journal | author=Buckley RH | title=Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution | journal=Annu Rev Immunol | year=2004 | pages=625–55 | volume=22  | pmid=15032591 | doi=10.1146/annurev.immunol.22.012703.104614}}
* {{cite journal | vauthors=Kalman L, Lindegren ML, Kobrynski L, Vogt R, Hannon H, Howard JT, Buckley R | title=Mutations in genes required for T-cell development: IL7R, CD45, IL2RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HuGE review | journal=Genet Med | year=2004 | pages=16–26 | volume=6 | issue=1  | pmid=14726805 | doi=10.1097/01.GIM.0000105752.80592.A3| doi-access=free }}
*{{cite journal  | vauthors=Ellery JM, Nicholls PJ |title=Alternate signalling pathways from the interleukin-2 receptor |journal=Cytokine Growth Factor Rev. |volume=13 |issue= 1 |pages= 27–40 |year= 2002 |pmid= 11750878 |doi=10.1016/S1359-6101(01)00023-5  }}
*{{cite journal | vauthors = Takeshita T, Asao H, Ohtani K, Ishii N, Kumaki S, Tanaka N, Munakata H, Nakamura M, Sugamura K | title = Cloning of the gamma chain of the human IL-2 receptor | journal = Science | volume = 257 | issue = 5068 | pages = 379–82 |date=July 1992 | pmid = 1631559 | doi = 10.1126/science.1631559 | bibcode = 1992Sci...257..379T }}
*{{cite journal | vauthors = Burton J, Goldman CK, Rao P, Moos M, Waldmann TA | title = Association of intercellular adhesion molecule 1 with the multichain high-affinity interleukin 2 receptor | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 87 | issue = 18 | pages = 7329–33 |date=September 1990 | pmid = 1976256 | pmc = 54737 | doi = 10.1073/pnas.87.18.7329 | bibcode = 1990PNAS...87.7329B | doi-access = free }}
*{{cite journal | vauthors = Oyaizu N, Chirmule N, Kalyanaraman VS, Hall WW, Pahwa R, Shuster M, Pahwa S | title = Human immunodeficiency virus type 1 envelope glycoprotein gp120 produces immune defects in CD4+ T lymphocytes by inhibiting interleukin 2 mRNA | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 87 | issue = 6 | pages = 2379–83 |date=March 1990 | pmid = 2315327 | pmc = 53690 | doi = 10.1073/pnas.87.6.2379 | bibcode = 1990PNAS...87.2379O | doi-access = free }}
*{{cite journal | vauthors = Kornfeld H, Cruikshank WW, Pyle SW, Berman JS, Center DM | title = Lymphocyte activation by HIV-1 envelope glycoprotein | journal = Nature | volume = 335 | issue = 6189 | pages = 445–8 |date=September 1988 | pmid = 2843775 | doi = 10.1038/335445a0 | bibcode = 1988Natur.335..445K | s2cid = 4326650 | url = https://zenodo.org/record/1233075}}
*{{cite journal  | vauthors=Bamborough P, Hedgecock CJ, Richards WG |title=The interleukin-2 and interleukin-4 receptors studied by molecular modelling |journal=Structure |volume=2 |issue= 9 |pages= 839–51 |year= 1995 |pmid= 7529123 |doi=10.1016/S0969-2126(94)00085-9  |doi-access= }}
*{{cite journal | vauthors = Clark PA, Lester T, Genet S, Jones AM, Hendriks R, Levinsky RJ, Kinnon C | title = Screening for mutations causing X-linked severe combined immunodeficiency in the IL-2R gamma chain gene by single-strand conformation polymorphism analysis | journal = Hum. Genet. | volume = 96 | issue = 4 | pages = 427–32 |date=October 1995 | pmid = 7557965 | doi = 10.1007/BF00191801 | s2cid = 29039832 }}
*{{cite journal | vauthors = Pepper AE, Buckley RH, Small TN, Puck JM | title = Two mutational hotspots in the interleukin-2 receptor gamma chain gene causing human X-linked severe combined immunodeficiency | journal = Am. J. Hum. Genet. | volume = 57 | issue = 3 | pages = 564–71 |date=September 1995 | pmid = 7668284 | pmc = 1801277 }}
*{{cite journal | vauthors = Ohbo K, Takasawa N, Ishii N, Tanaka N, Nakamura M, Sugamura K | title = Functional analysis of the human interleukin 2 receptor gamma chain gene promoter | journal = J. Biol. Chem. | volume = 270 | issue = 13 | pages = 7479–86 |date=March 1995 | pmid = 7706294 | doi = 10.1074/jbc.270.13.7479 | doi-access = free }}
*{{cite journal | vauthors = Puck JM, Pepper AE, Bédard PM, Laframboise R | title = Female germ line mosaicism as the origin of a unique IL-2 receptor gamma-chain mutation causing X-linked severe combined immunodeficiency | journal = J. Clin. Invest. | volume = 95 | issue = 2 | pages = 895–9 |date=February 1995 | pmid = 7860773 | pmc = 295580 | doi = 10.1172/JCI117740 }}
*{{cite journal | vauthors = DiSanto JP, Rieux-Laucat F, Dautry-Varsat A, Fischer A, de Saint Basile G | title = Defective human interleukin 2 receptor gamma chain in an atypical X chromosome-linked severe combined immunodeficiency with peripheral T cells | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 91 | issue = 20 | pages = 9466–70 |date=September 1994 | pmid = 7937790 | pmc = 44833 | doi = 10.1073/pnas.91.20.9466 | bibcode = 1994PNAS...91.9466D | doi-access = free }}
*{{cite journal | vauthors = Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O | title = Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID | journal = Science | volume = 266 | issue = 5187 | pages = 1042–5 |date=November 1994 | pmid = 7973658 | doi = 10.1126/science.7973658 | bibcode = 1994Sci...266.1042R | url = https://zenodo.org/record/1231239 }}
*{{cite journal | vauthors = Ishii N, Asao H, Kimura Y, Takeshita T, Nakamura M, Tsuchiya S, Konno T, Maeda M, Uchiyama T, Sugamura K | title = Impairment of ligand binding and growth signaling of mutant IL-2 receptor gamma-chains in patients with X-linked severe combined immunodeficiency | journal = J. Immunol. | volume = 153 | issue = 3 | pages = 1310–7 |date=August 1994 | doi = 10.4049/jimmunol.153.3.1310 | pmid = 8027558 | s2cid = 24092176 }}
*{{cite journal | vauthors = Johnson K, Choi Y, Wu Z, Ciardelli T, Granzow R, Whalen C, Sana T, Pardee G, Smith K, Creasey A | title = Soluble IL-2 receptor beta and gamma subunits: ligand binding and cooperativity | journal = Eur. Cytokine Netw. | volume = 5 | issue = 1 | pages = 23–34 | year = 1994 | pmid = 8049354 }}
*{{cite journal | vauthors = Markiewicz S, Subtil A, Dautry-Varsat A, Fischer A, de Saint Basile G | title = 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 | journal = Genomics | volume = 21 | issue = 1 | pages = 291–3 |date=May 1994 | pmid = 8088810 | doi = 10.1006/geno.1994.1265 }}
*{{cite journal | vauthors = Kondo M, Takeshita T, Ishii N, Nakamura M, Watanabe S, Arai K, Sugamura K | title = Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4 | journal = Science | volume = 262 | issue = 5141 | pages = 1874–7 |date=December 1993 | pmid = 8266076 | doi = 10.1126/science.8266076 | bibcode = 1993Sci...262.1874K }}
{{refend}}

==External links==
* {{MeshName|Interleukin+Receptor+Common+gamma+Subunit}}
* {{PDBe-KB2|P31785|Human Cytokine receptor common subunit gamma}}

{{PDB Gallery|geneid=3561}}
{{Clusters of differentiation}}
{{Cytokine receptors}}
{{Interleukin receptor modulators}}

{{DEFAULTSORT:Common Gamma Chain}}
[[Category:Type I cytokine receptors]]
[[Category:Immune system]]