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

Abstract

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.

A redox state-dictated signalling pathway deciphers the malignant cell specificity of CD40-mediated apoptosis

“…Although the importance of ASK1 in apoptosis triggered by TNFR members has been reported, 31 this is the first such demonstration for CD40. More importantly, CD40 not only activates ASK1 but concurrently causes down-regulation of Trx expression; to our knowledge a first such demonstration for a TNFR member.…”

“…23 Despite evidence supporting a role for ROS in signalling and apoptosis triggered by the death receptor subgroup of the TNFR family, 31 the role of ROS in CD40 signalling remains largely unknown particularly in epithelial cells. 32 Therefore, we examined whether CD40 signalling regulates cellular ROS levels in order to activate ASK1 and provoke subsequent apoptosis.…”

“…the degree of receptor activation or cross-linking) affects or determines the outcome of receptor ligation. Highly cross-linked agonistic antibodies, cross-linked soluble recombinant ligands and particularly membrane-presented ligand (achieved by co-culture of target cells with growth-arrested, ligand-expressing third-party cells) induce a greater extent of carcinoma cell death in vitro in comparison to non-cross-linked agonists 31 but no mechanistic basis is available. In the context of CD40, our present findings in combination with previous observations suggest that these differences are not only based on TRAF3 stabilisation capacity but also concomitant activation of the Nox subunit p40phox.…”

CD40 induces renal cell carcinoma-specific differential regulation of TRAF proteins, ASK1 activation and JNK/p38-mediated, ROS-dependent mitochondrial apoptosis

“…CD40 lacks kinase activity and related intracellular signalling motifs, thus utilises adapter molecules TNFR-associated factors (TRAFs) for signal transduction 4 , with TRAF2 and TRAF3 being the main TRAF proteins that play significant and often opposing roles in CD40 signalling 5 . After CD40L-mediated activation, CD40 translocates to lipid rafts, where it associates with various TRAFs 6 to activate downstream mitogen-activated protein kinases (MAPKs) 7,8 .…”

“…Recent studies provided evidence that the consequences of CD40 ligation may differ in normal and malignant cells, thus its effects may be highly context-specific 5 . Moreover, the ‘quality’ of the CD40 signal may determine whether CD40L–CD40 interactions are pro-apoptotic: extensive receptor cross-linking by membrane-presented CD40L (mCD40L) causes extensive apoptosis, while soluble agonists (e.g.…”