Lymphotoxin beta explained

Lymphotoxin-beta (LT-beta) also known as tumor necrosis factor C (TNF-C) is a protein that in humans is encoded by the LTB gene.^{[1] [2] [3]}

Function

Lymphotoxin beta is a type II membrane protein of the TNF family. It anchors lymphotoxin-alpha to the cell surface through heterotrimer formation. The predominant form on the lymphocyte surface is the lymphotoxin-alpha 1/beta 2 complex (e.g. 1 molecule alpha/2 molecules beta) and this complex is the primary ligand for the lymphotoxin-beta receptor. The minor complex is lymphotoxin-alpha 2/beta 1. LTB is an inducer of the inflammatory response system and involved in normal development of lymphoid tissue. Lymphotoxin-beta isoform b is unable to complex with lymphotoxin-alpha suggesting a function for lymphotoxin-beta which is independent of lymphotoxin-alpha. Alternative splicing results in multiple transcript variants encoding different isoforms.^[3]

Pro-tumorigenic function of membrane LT is clearly established: mice with overexpression of LTα or LTβ showed increased tumor growth and metastasis in several models of cancer. However, these studies utilized mice with complete LTα gene deficiency that did not allow to distinguish effects of soluble versus membrane-associated LT.^[4]

Interactions

LTB has been shown to interact with Lymphotoxin alpha.^{[5] [6] [7]}

Further reading

• Messer G, Spengler U, Jung MC, Honold G, Blömer K, Pape GR, Riethmüller G, Weiss EH . Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production . The Journal of Experimental Medicine . 173 . 1 . 209–19 . Jan 1991 . 1670638 . 2118757 . 10.1084/jem.173.1.209 .
• Abraham LJ, Du DC, Zahedi K, Dawkins RL, Whitehead AS . Haplotypic polymorphisms of the TNFB gene . Immunogenetics . 33 . 1 . 50–3 . 1991 . 1671667 . 10.1007/BF00211695 . 38756894 .
• Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarrett-Nedwin J, Pennica D, Goeddel DV, Gray PW . Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization . Nucleic Acids Research . 13 . 17 . 6361–73 . Sep 1985 . 2995927 . 321958 . 10.1093/nar/13.17.6361 .
• Holzinger I, de Baey A, Messer G, Kick G, Zwierzina H, Weiss EH . Cloning and genomic characterization of LST1: a new gene in the human TNF region . Immunogenetics . 42 . 5 . 315–22 . 1995 . 7590964 . 10.1007/BF00179392 . 19916860 .
• Peelman LJ, Chardon P, Nunes M, Renard C, Geffrotin C, Vaiman M, Van Zeveren A, Coppieters W, van de Weghe A, Bouquet Y . The BAT1 gene in the MHC encodes an evolutionarily conserved putative nuclear RNA helicase of the DEAD family . Genomics . 26 . 2 . 210–8 . Mar 1995 . 7601445 . 10.1016/0888-7543(95)80203-X .
• Browning JL, Dougas I, Ngam-ek A, Bourdon PR, Ehrenfels BN, Miatkowski K, Zafari M, Yampaglia AM, Lawton P, Meier W . Characterization of surface lymphotoxin forms. Use of specific monoclonal antibodies and soluble receptors . Journal of Immunology . 154 . 1 . 33–46 . Jan 1995 . 10.4049/jimmunol.154.1.33 . 7995952 . 22313274 . free .
• Albertella MR, Campbell RD . Characterization of a novel gene in the human major histocompatibility complex that encodes a potential new member of the I kappa B family of proteins . Human Molecular Genetics . 3 . 5 . 793–9 . May 1994 . 8081366 . 10.1093/hmg/3.5.793 .
• Iris FJ, Bougueleret L, Prieur S, Caterina D, Primas G, Perrot V, Jurka J, Rodriguez-Tome P, Claverie JM, Dausset J . Dense Alu clustering and a potential new member of the NF kappa B family within a 90 kilobase HLA class III segment . Nature Genetics . 3 . 2 . 137–45 . Feb 1993 . 8499947 . 10.1038/ng0293-137 . 33041319 .
• Nakamura T, Tashiro K, Nazarea M, Nakano T, Sasayama S, Honjo T . The murine lymphotoxin-beta receptor cDNA: isolation by the signal sequence trap and chromosomal mapping . Genomics . 30 . 2 . 312–9 . Nov 1995 . 8586432 . 10.1006/geno.1995.9872 . 2433/202166 . free .
• Utans U, Quist WC, McManus BM, Wilson JE, Arceci RJ, Wallace AF, Russell ME . Allograft inflammatory factory-1. A cytokine-responsive macrophage molecule expressed in transplanted human hearts . Transplantation . 61 . 9 . 1387–92 . May 1996 . 8629302 . 10.1097/00007890-199605150-00018 . free .
• Nalabolu SR, Shukla H, Nallur G, Parimoo S, Weissman SM . Genes in a 220-kb region spanning the TNF cluster in human MHC . Genomics . 31 . 2 . 215–22 . Jan 1996 . 8824804 . 10.1006/geno.1996.0034 . free .
• Laham N, Van Dunné F, Abraham LJ, Farrugia W, Bendtzen K, Brennecke SP, Rice GE . Tumor necrosis factor-beta in human pregnancy and labor . Journal of Reproductive Immunology . 33 . 1 . 53–69 . Apr 1997 . 9185077 . 10.1016/S0165-0378(97)01012-7 .
• Warzocha K, Renard N, Charlot C, Bienvenu J, Coiffier B, Salles G . Identification of two lymphotoxin beta isoforms expressed in human lymphoid cell lines and non-Hodgkin's lymphomas . Biochemical and Biophysical Research Communications . 238 . 2 . 273–6 . Sep 1997 . 9299492 . 10.1006/bbrc.1997.7277 .
• Browning JL, Sizing ID, Lawton P, Bourdon PR, Rennert PD, Majeau GR, Ambrose CM, Hession C, Miatkowski K, Griffiths DA, Ngam-ek A, Meier W, Benjamin CD, Hochman PS . Characterization of lymphotoxin-alpha beta complexes on the surface of mouse lymphocytes . Journal of Immunology . 159 . 7 . 3288–98 . Oct 1997 . 10.4049/jimmunol.159.7.3288 . 9317127 . 25608697 . free .
• de Baey A, Fellerhoff B, Maier S, Martinozzi S, Weidle U, Weiss EH . Complex expression pattern of the TNF region gene LST1 through differential regulation, initiation, and alternative splicing . Genomics . 45 . 3 . 591–600 . Nov 1997 . 9367684 . 10.1006/geno.1997.4963 .
• Shiina T, Tamiya G, Oka A, Yamagata T, Yamagata N, Kikkawa E, Goto K, Mizuki N, Watanabe K, Fukuzumi Y, Taguchi S, Sugawara C, Ono A, Chen L, Yamazaki M, Tashiro H, Ando A, Ikemura T, Kimura M, Inoko H . Nucleotide sequencing analysis of the 146-kilobase segment around the IkBL and MICA genes at the centromeric end of the HLA class I region . Genomics . 47 . 3 . 372–82 . Feb 1998 . 9480751 . 10.1006/geno.1997.5114 .
• Bodor J, Habener JF . Role of transcriptional repressor ICER in cyclic AMP-mediated attenuation of cytokine gene expression in human thymocytes . The Journal of Biological Chemistry . 273 . 16 . 9544–51 . Apr 1998 . 9545284 . 10.1074/jbc.273.16.9544 . free .
• Neville MJ, Campbell RD . A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC . Journal of Immunology . 162 . 8 . 4745–54 . Apr 1999 . 10.4049/jimmunol.162.8.4745 . 10202016 . 46517924 . free .

Notes and References

1. Browning JL, Ngam-ek A, Lawton P, DeMarinis J, Tizard R, Chow EP, Hession C, O'Brine-Greco B, Foley SF, Ware CF . Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface . Cell . 72 . 6 . 847–56 . Mar 1993 . 7916655 . 10.1016/0092-8674(93)90574-A . 28961163 .
2. Browning JL, Androlewicz MJ, Ware CF . Lymphotoxin and an associated 33-kDa glycoprotein are expressed on the surface of an activated human T cell hybridoma . Journal of Immunology . 147 . 4 . 1230–7 . Aug 1991 . 10.4049/jimmunol.147.4.1230 . 1714477 . 6160376 . free .
3. Web site: Entrez Gene: LTB lymphotoxin beta (TNF superfamily, member 3).
4. Korneev. KV. Atretkhany. KN. Drutskaya. MS. Grivennikov. SI. Kuprash. DV. Nedospasov. SA. TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis.. Cytokine. January 2017. 89. 127–135. 10.1016/j.cyto.2016.01.021. 26854213.
5. Williams-Abbott L, Walter BN, Cheung TC, Goh CR, Porter AG, Ware CF . The lymphotoxin-alpha (LTalpha) subunit is essential for the assembly, but not for the receptor specificity, of the membrane-anchored LTalpha1beta2 heterotrimeric ligand . The Journal of Biological Chemistry . 272 . 31 . 19451–6 . Aug 1997 . 9235946 . 10.1074/jbc.272.31.19451 . free .
6. Browning JL, Sizing ID, Lawton P, Bourdon PR, Rennert PD, Majeau GR, Ambrose CM, Hession C, Miatkowski K, Griffiths DA, Ngam-ek A, Meier W, Benjamin CD, Hochman PS . Characterization of lymphotoxin-alpha beta complexes on the surface of mouse lymphocytes . Journal of Immunology . 159 . 7 . 3288–98 . Oct 1997 . 10.4049/jimmunol.159.7.3288 . 9317127 . 25608697 . free .
7. Browning JL, Dougas I, Ngam-ek A, Bourdon PR, Ehrenfels BN, Miatkowski K, Zafari M, Yampaglia AM, Lawton P, Meier W . Characterization of surface lymphotoxin forms. Use of specific monoclonal antibodies and soluble receptors . Journal of Immunology . 154 . 1 . 33–46 . Jan 1995 . 10.4049/jimmunol.154.1.33 . 7995952 . 22313274 . free .