The molecular architecture of the TNF superfamily

Bodmer, Jean-Luc; Schneider, Pascal; Tschopp, Jürg

doi:10.1016/s0968-0004(01)01995-8

Cited by 806 publications

(742 citation statements)

References 56 publications

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“…1 TNF family ligands are primarily expressed as trimeric type II transmembrane proteins and are often processed into soluble variants that are also organized as trimers. 1,2 Although shedding of some TNF ligands does not interfere with their capability to activate their corresponding receptors and might be even important for their physiological function, other TNF ligands become inactivated by proteolytic processing. 2 Soluble TNF ligands that are not or only poorly active still interact with their cognate receptors.…”

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confidence: 99%

“…1,2 Although shedding of some TNF ligands does not interfere with their capability to activate their corresponding receptors and might be even important for their physiological function, other TNF ligands become inactivated by proteolytic processing. 2 Soluble TNF ligands that are not or only poorly active still interact with their cognate receptors. For example, the soluble forms of TNF, CD95L, TRAIL, and CD40L interact with TNFR2, CD95, TRAILR2, and CD40, respectively, but do not or only poorly activate signaling by these receptors.…”

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confidence: 99%

“…[6][7][8] The structural hallmark of the ligands of the TNF family is the carboxy-terminal 'TNF homology domain', which is part of both the transmembrane and soluble forms of TNF ligands. [1][2] The TNF homology domains (THDs) of the various TNF ligands are composed of a framework of aromatic and hydrophobic residues that adopt an almost identical tertiary fold and cause self association into trimers. [1][2] The THD also mediates receptor binding.…”

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confidence: 99%

“…[1][2] The TNF homology domains (THDs) of the various TNF ligands are composed of a framework of aromatic and hydrophobic residues that adopt an almost identical tertiary fold and cause self association into trimers. [1][2] The THD also mediates receptor binding. In general, trimeric ligands of the TNF family bind to three molecules of their corresponding receptor(s).…”

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Enforced covalent trimerization increases the activity of the TNF ligand family members TRAIL and CD95L

et al. 2007

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Variants of human TRAIL (hTRAIL) and human CD95L (hCD95L), encompassing the TNF homology domain (THD), interact with the corresponding receptors and stimulate CD95 and TRAILR2 signaling after cross-linking. The murine counterparts (mTRAIL, mCD95L) showed no or only low receptor binding and were inactive/poorly active after cross-linking. The stalk region preceding the THD of mCD95L conferred secondary aggregation and restored CD95 activation in the absence of cross-linking. A corresponding variant of mTRAIL, however, was still not able to activate TRAIL death receptors, but gained good activity after cross-linking. Notably, disulfide-bonded fusion proteins of the THD of mTRAIL and mCD95L with a subdomain of the tenascin-C (TNC) oligomerization domain, which still assembled into trimers, efficiently interacted with their cognate cellular receptors and robustly stimulated CD95 and TRAILR2 signaling after secondary cross-linking. Introduction of the TNC domain also further enhanced the activity of THD encompassing variants of hTRAIL and hCD95L. Thus, spatial fixation of the N-terminus of the THD appears necessary in some TNF ligands to ensure proper receptor binding. This points to yet unanticipated functions of the stalk and/or transmembrane region of TNF ligands for the functionality of these molecules and offers a broadly applicable option to generate recombinant soluble ligands of the TNF family with superior activity. Ligands of the tumor necrosis factor (TNF) family fulfill crucial roles in the immune system, but have also been implicated in the development of epithelial and endothelial structures. 1 TNF family ligands are primarily expressed as trimeric type II transmembrane proteins and are often processed into soluble variants that are also organized as trimers. 1,2 Although shedding of some TNF ligands does not interfere with their capability to activate their corresponding receptors and might be even important for their physiological function, other TNF ligands become inactivated by proteolytic processing. 2 Soluble TNF ligands that are not or only poorly active still interact with their cognate receptors. For example, the soluble forms of TNF, CD95L, TRAIL, and CD40L interact with TNFR2, CD95, TRAILR2, and CD40, respectively, but do not or only poorly activate signaling by these receptors. [3][4][5][6] Notably, inactive or poorly active soluble TNF ligands can be converted into highly active molecules by artificially increasing their avidity. For example, soluble flag-tagged variants of TNF, CD95L, TRAIL, and CD40L stimulate robust signaling by TNFR2, CD95, TRAILR2, and CD40, respectively, provided they were cross-linked with the Flag-specific mAb M2. Likewise, hexameric and dodecameric fusion proteins of soluble CD95L and soluble CD40L as well as non-specifically aggregated preparations of TNF ligands produced in E. coli display high activity. [6][7][8] The structural hallmark of the ligands of the TNF family is the carboxy-terminal 'TNF homology domain', which is part of both the transmembrane and s...

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Enforced covalent trimerization increases the activity of the TNF ligand family members TRAIL and CD95L

et al. 2007

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“…TNFLs are type II transmembrane proteins that contain an intracellular N-terminus and extracellular C-terminus with the C-terminus region characterised by a conserved TNF homology domain (THD) (2,3). TNFα is expressed in full-length on the cell surface as a 26kDa membrane ligand (mTNFα) and as a 17kDa soluble cytokine (sTNFα) after shedding.…”

Section: Tnflsmentioning

confidence: 99%

Regulation of cell fate by lymphotoxin (LT) receptor signalling: Functional differences and similarities of the LT system to other TNF superfamily (TNFSF) members

Albarbar

Dunnill

Georgopoulos

2015

Cytokine & Growth Factor Reviews

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The role of TNFR family members in regulating cell fate both in the immune system and in non-lymphoid tissues has been under extensive research for decades. Moreover, the ability of several family members (death receptors) to induce death (mainly via apoptosis) represents a promising target for cancer therapy. Many studies have focused mostly on death receptors such as TNFRI, Fas and TRAIL-R due to their strong pro-apoptotic potential.Yet, cell death can be triggered via non-classical death receptors, and the Lymphotoxin (LT) system represents a very good example of such a TNFR subfamily. Here we provide a comprehensive review of intracellular signalling pathways and cellular responses to LTspecific signalling, and compare for the first time the LT system to other TNFRs, such as CD40. Our aim is to highlight that non-classical TNFR-TNFL dyads such as the LT system demonstrate more complex, cell-type and context-specific capabilities. Understanding these complexities will permit a better understanding of the biological mechanisms via which nondeath domain-containing TNFRs induce cell death, but may also allow the design of better therapeutic strategies.

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Recruitment of TNF ligands to lipid rafts is mediated by their physical association with caveolin‐1

et al. 2021

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Activities of the tumour necrosis factor (TNF) family members are associated with their targeting to lipid rafts, specialised regions of the plasma membrane. Herein, we investigated the physical association of TNF and its family members cluster of differentiation 40 ligand (CD40L) and tumour necrosis factor‐related apoptosis‐inducing ligand with caveolin‐1, a lipid raft resident protein. We discovered that the intracellular domains of TNF and CD40L interact with caveolin‐1, and the membrane proximal region of TNF is required for the binding of caveolin‐1 domains. Full‐length TNF can form a complex with caveolin‐1 in membrane rafts of HeLa cells, and caveolin‐1 knockdown leads to impaired TNF transport to rafts. These findings provide the first evidence of a direct interaction between TNF, CD40L and caveolin‐1 and suggest that caveolin‐1 may be responsible for recruiting TNF to lipid rafts.

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The molecular architecture of the TNF superfamily

Cited by 806 publications

References 56 publications

Enforced covalent trimerization increases the activity of the TNF ligand family members TRAIL and CD95L

Enforced covalent trimerization increases the activity of the TNF ligand family members TRAIL and CD95L

Regulation of cell fate by lymphotoxin (LT) receptor signalling: Functional differences and similarities of the LT system to other TNF superfamily (TNFSF) members

Recruitment of TNF ligands to lipid rafts is mediated by their physical association with caveolin‐1

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