TNFSF9

TNFSF9
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2X29
Identifiers
Aliases	TNFSF9, 4-1BB-L, CD137L, TNLG5A, tumor necrosis factor superfamily member 9, TNF superfamily member 9
External IDs	OMIM: 606182; MGI: 1101058; HomoloGene: 55782; GeneCards: TNFSF9; OMA:TNFSF9 - orthologs
Gene location (Human)
Chr.	Chromosome 19 (human)
End	6,535,924 bp
Gene location (Mouse)
Chr.	Chromosome 17 (mouse)
End	57,414,757 bp
RNA expression pattern
	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;
	Top expressed in
	gastrula; ; decidua; ; blastocyst; ; embryo; ; embryo; ; cumulus cell; ; humerus; ; ventricular zone; ; medial ganglionic eminence; ; stroma of bone marrow;
	More reference expression data
	n/a
Gene ontology
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
Orthologs
	8744
	21950
	ENSG00000125657
	ENSMUSG00000035678
	P41273
	P41274
	NM_003811
	NM_009404
	NP_003802
	NP_033430
	Wikidata
View/Edit Human	View/Edit Mouse

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

TNFSF9 consists of an extracellular domain responsible for receptor binding, a transmembrane region, and a short intracellular domain, and can also exist in a soluble form when cleaved from the membrane. This structural organization enables TNFSF9 to function as a bidirectional signal transducer, facilitating costimulatory signaling crucial for T cell activation and immune response modulation.^[8]

Receptor/ligand complex

TNFSF9 forms a trimeric complex on the cell surface, which interacts with the 4-1BB (CD137) receptor on activated T lymphocytes. Each 4-1BB monomer binds to two 4-1BBL subunits via cysteine-rich domains (CRDs), with the CRD2 and CRD3 regions of 4-1BB engaging specific loops on 4-1BBL to stabilize the interaction through multiple hydrogen bonds.^[8]

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.^[9] 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.^[10]

Function

TNFSF9 plays a key role in immune cell interactions. TNFSF9 forms a trimeric complex on the cell surface, which interacts with the 4-1BB (CD137) receptor on activated T lymphocytes. Complex formation with its receptor enables TNFSF9 to function as a bidirectional signal transducer, facilitating costimulatory signaling crucial for T cell activation and immune response modulation.^[8]

Clinical significance

Early studies using the poorly immunogenic Ag104A sarcoma and highly tumorigenic P815 mastocytoma models provided the first systematic evidence that anti-4-1BB antibodies exert strong anti-tumor effects. These antibodies were found to significantly suppress tumor growth by enhancing cytotoxic T lymphocyte (CTL) activity. Subsequent research has consistently confirmed the role of 4-1BB signaling in promoting anti-tumor immunity.^[11]

The 4-1BB/4-1BBL interaction delivers costimulatory signals that enhance T-cell responses, a mechanism with significant implications for cancer immunotherapy. When combined with T-cell receptor signaling, this interaction stimulates both CD4⁺ and CD8⁺ T cells, contributing to effective anti-tumor responses.^[6] However, in human CD28⁻ T cells, 4-1BB signaling can promote expansion of this subset, which is associated with adverse outcomes in cancer and other diseases. As a result, modulating this pathway represents a promising therapeutic strategy.^[12]

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. 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): 215–226. doi:10.1038/sj.cgt.7700670. PMID 14671675. S2CID 11429744.
^ Lotze M (2001). Dendritic Cells. Boston: Academic Press. ISBN 978-0-12-455851-9.
^ ^a ^b ^c Choi BK, Lee HW (2020). "The Murine CD137/CD137 Ligand Signalosome: A Signal Platform Generating Signal Complexity". Frontiers in Immunology. 11: 553715. doi:10.3389/fimmu.2020.553715. PMC 7758191. PMID 33362756.
^ 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, 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. 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): 446–454. doi:10.1002/immu.200310020. PMID 12645943. S2CID 38395011.

External links

4-1BB+Ligand at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This biochemistry article is a stub. You can help Wikipedia by expanding it.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000125657 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000035678 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[Singh_2024-5] Singh R, Kim YH, Lee SJ, Eom HS, Choi BK (Feb 2024). "4-1BB immunotherapy: advances and hurdles". Experimental & Molecular Medicine. 56 (1): 32–39. doi:10.1038/s12276-023-01136-4. PMC 10834507. PMID 38172595.

[Cheuk_2004-6] Cheuk AT, Mufti GJ, Guinn BA (March 2004). "Role of 4-1BB:4-1BB ligand in cancer immunotherapy". Cancer Gene Therapy. 11 (3): 215–226. doi:10.1038/sj.cgt.7700670. PMID 14671675. S2CID 11429744.

[7] Lotze M (2001). Dendritic Cells. Boston: Academic Press. ISBN 978-0-12-455851-9.

[Choi_2020-8] Choi BK, Lee HW (2020). "The Murine CD137/CD137 Ligand Signalosome: A Signal Platform Generating Signal Complexity". Frontiers in Immunology. 11: 553715. doi:10.3389/fimmu.2020.553715. PMC 7758191. PMID 33362756.

[9] 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.

[10] 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. ISSN 2211-1247. PMID 30355497.

[11] 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.

[12] Bukczynski J, Wen T, Watts TH (February 2003). "Costimulation of human CD28- T cells by 4-1BB ligand". European Journal of Immunology. 33 (2): 446–454. doi:10.1002/immu.200310020. PMID 12645943. S2CID 38395011.

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