TNFSF9

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]

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)[1] Band 19p13.3 Start 6,531,026 bp[1] End 6,535,924 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17|17 D Start 57,412,325 bp[2] End 57,414,757 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) 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 BioGPS 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 Species Human Mouse Entrez 8744 21950 Ensembl ENSG00000125657 ENSMUSG00000035678 UniProt P41273 P41274 RefSeq (mRNA) NM_003811 NM_009404 RefSeq (protein) NP_003802 NP_033430 Location (UCSC) Chr 19: 6.53 – 6.54 Mb Chr 17: 57.41 – 57.41 Mb PubMed search [3] [4]
Wikidata
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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]

See also

• CD137