Mammalian protein found in Homo sapiens
TNFSF9 |
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Available structures |
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PDB | Ortholog search: PDBe RCSB |
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Identifiers |
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Aliases | TNFSF9, 4-1BB-L, CD137L, TNLG5A, tumor necrosis factor superfamily member 9, TNF superfamily member 9 |
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External IDs | OMIM: 606182; MGI: 1101058; HomoloGene: 55782; GeneCards: TNFSF9; OMA:TNFSF9 - orthologs |
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Gene location (Human) |
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| Chr. | Chromosome 19 (human)[1] |
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| Band | 19p13.3 | Start | 6,531,026 bp[1] |
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End | 6,535,924 bp[1] |
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Gene location (Mouse) |
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| Chr. | Chromosome 17 (mouse)[2] |
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| Band | 17|17 D | Start | 57,412,325 bp[2] |
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End | 57,414,757 bp[2] |
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RNA expression pattern |
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Bgee | Human | Mouse (ortholog) |
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Top expressed in | - buccal mucosa cell
- testicle
- internal globus pallidus
- vagina
- Brodmann area 9
- right frontal lobe
- upper lobe of left lung
- prefrontal cortex
- muscle of thigh
- cerebellar hemisphere
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| Top expressed in | - gastrula
- decidua
- blastocyst
- embryo
- embryo
- cumulus cell
- humerus
- ventricular zone
- medial ganglionic eminence
- stroma of bone marrow
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| More reference expression data |
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BioGPS | |
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Gene ontology |
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Molecular function | - tumor necrosis factor receptor binding
- cytokine activity
- signaling receptor binding
- tumor necrosis factor receptor superfamily binding
| Cellular component | - integral component of membrane
- membrane
- extracellular space
- plasma membrane
| Biological process | - cell-cell signaling
- cell population proliferation
- immune response
- signal transduction
- apoptotic process
- positive regulation of activated T cell proliferation
- positive regulation of cytotoxic T cell differentiation
- tumor necrosis factor-mediated signaling pathway
- regulation of signaling receptor activity
- regulation of T cell proliferation
- regulation of apoptotic process
| Sources:Amigo / QuickGO |
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Orthologs |
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Species | Human | Mouse |
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Entrez | | |
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Ensembl | | |
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UniProt | | |
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RefSeq (mRNA) | | |
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RefSeq (protein) | | |
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Location (UCSC) | Chr 19: 6.53 – 6.54 Mb | Chr 17: 57.41 – 57.41 Mb |
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PubMed search | [3] | [4] |
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Wikidata |
View/Edit Human | View/Edit Mouse |
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Tumor necrosis factor ligand superfamily member 9 also known as 4-1BB ligand or 4-1BBL or CD137L is a protein that in humans is encoded by the TNFSF9 gene.[5]
4-1BBL is a type 2 transmembrane glycoprotein receptor that is found on APCs (antigen presenting cells) and binds to 4-1BB (also known as CD137). The 4-1BB/4-1BBL complex belongs to the TNFR:TNF superfamily,[6] which is expressed on activated T Lymphocytes.[7]
Structure of 4-1BB/4-1BBL complex
The 4-1BB/4-1BBL complex consists of three monomeric 4-1BBs bound to a trimeric 4-1BBL. Each 4-1BB monomer binds to two 4-1BBLs via cysteine-rich domains (CRDs). The interaction between 4-1BB and the second 4-1BBL is required to stabilize their interactions.[8] The link with 4-1BBL is largely made up of amino acids from the dynamic loops of the CRD2 and the β sheet of CRD3 of 4-1BB, according to a detailed study of the binding between the 4-1BB and 4-1BBL interface. CRD2 amino acids (T61, Q67, and K69) interact with the AA′ loop (Y110 and G114) and the intra-H-strand loop (Q227 and Q230) of 4-1BBL to form various hydrogen bond interactions.[9]
Application to cancer immunotherapy
Studies on the poorly immunogenic Ag104A sarcoma and the extremely tumorigenic P815 mastocytoma provided the first systematic proof that anti-4-1BB antibodies have potent anti-tumor effects. Anti-4-1BB administration to mice with the aforementioned tumors was shown to substantially inhibit tumor growth by increasing CTL activity. In the years to come, more studies verified and legitimized the effect of 4-1BB signaling to inhibit tumor growth.[10]
The interaction between 4-1BB and 4-1BBL provide costimulatory signals to a variety of T cells, which can be used to discover cancer immunotherapy. The 4-1BB/4-1BBL complex together with a signal provided by a T-cell receptor can provide costimulatory signals to CD4+ and CD8+ T cells in mice, leading to the activation of CD4+ and CD8+ T cells. The activation of CD8+ T cells is essential in antitumor immunity.[6] The 4-1BB/4-1BBL complex with the help of T-cell receptor signals can co-stimulate human CD28− T cells and trigger the increase in CD28− T cells. Unlike the activation of CD8+ T cells, the proliferation of CD28− T cells can negatively affect cancer state and other diseases. Therefore, this pathway can be targeted for immunotherapy.[11]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000125657 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035678 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Singh R, Kim YH, Lee SJ, Eom HS, Choi BK (Feb 2024). "4-1BB immunotherapy: advances and hurdles". Experimental & Molecular Medicine volume. 56 (1): 32–39. doi:10.1038/s12276-023-01136-4. PMC 10834507. PMID 38172595.
- ^ a b Cheuk AT, Mufti GJ, Guinn BA (March 2004). "Role of 4-1BB:4-1BB ligand in cancer immunotherapy". Cancer Gene Therapy. 11 (3): 215–26. doi:10.1038/sj.cgt.7700670. PMID 14671675. S2CID 11429744.
- ^ Lotze M (2001). Dendritic Cells. Boston: Academic Press. ISBN 0-12-455851-8.
- ^ Li Y, Tan S, Zhang C, Chai Y, He M, Zhang CW, et al. (October 2018). "Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab". Cell Reports. 25 (4): 909–920.e4. doi:10.1016/j.celrep.2018.09.073. PMID 30355497.
- ^ Li Y, Tan S, Zhang C, Chai Y, He M, Zhang CW, Wang Q, Tong Z, Liu K, Lei Y, Liu WJ (October 2018). "Limited Cross-Linking of 4-1BB by 4-1BB Ligand and the Agonist Monoclonal Antibody Utomilumab". Cell Reports. 25 (4): 909–920.e4. doi:10.1016/j.celrep.2018.09.073. ISSN 2211-1247. PMID 30355497.
- ^ Vinay DS, Kwon BS (2012-05-01). "Immunotherapy of Cancer with 4-1BB". Molecular Cancer Therapeutics. 11 (5): 1062–1070. doi:10.1158/1535-7163.MCT-11-0677. ISSN 1535-7163. PMID 22532596.
- ^ Bukczynski J, Wen T, Watts TH (February 2003). "Costimulation of human CD28- T cells by 4-1BB ligand". European Journal of Immunology. 33 (2): 446–54. doi:10.1002/immu.200310020. PMID 12645943. S2CID 38395011.
External links
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By family | |
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By function/ cell | |
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Chemokine | |
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CSF | |
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Interferon | IFNAR (α/β, I) | - Agonists: Albinterferon
- Interferon alpha (interferon alfa, IFN-α)
- Interferon alfa (IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA21)
- Interferon alfa 2a
- Interferon alfa 2b
- Interferon alfa n1
- Interferon alfacon-1
- Interferon alpha-n3
- Interferon beta (IFN-β) (IFNB1, IFNB3)
- Interferon beta 1a
- Interferon beta 1b
- Interferon kappa (IFN-ε/κ/τ/ζ, IFNK)
- Interferon omega (IFN-ω, IFNW1)
- Peginterferon alfa-2a
- Peginterferon alfa-2b
- Decoy receptors: Bifarcept
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IFNGR (γ, II) | |
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IFNLR (λ, III) | - See IL-28R (IFNLR) here instead.
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Interleukin | |
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TGFβ | |
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TNF | |
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Others | |
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