Autoinhibitory structure of preligand association state implicates a new strategy to attain effective DR5 receptor activation

Du, Gang; Zhao, Linlin; Zheng, Yumei; Belfetmi, Anissa; Cai, Tao; Xu, Bo-Ying; Heyninck, Karen; Heede, Kim Van Den; Buyse, Marie-Ange; Fontana, Pietro; Bowman, Michael R.; Lin, Lih-Ling; Wu, Hao; Chou, James J.

doi:10.1038/s41422-022-00755-2

Cited by 6 publications

(9 citation statements)

References 66 publications

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“…Regardless of the modus operandi required for engaging cell death by these receptors, the latter have been found to form dimers or trimers, due to spontaneous self-association of their N-terminal extracellular domain, called pre-ligand assembly domain (PLAD) [ 129 , 130 ], which is generally present in the first cysteine-rich domain of some TNFSFRs ( Figure 1 ). By favouring ligand-independent receptor multimerizations, the PLAD limits apoptosis induced by TRAIL due to DR5 homodimerization [ 131 ], or the formation of heteromeric DR4, DR5, DcR1 or DcR2 complexes [ 42 , 56 , 132 ]. These self-association motifs have recently been demonstrated to be targetable.…”

Section: The Trail Systemmentioning

confidence: 99%

TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling

Guerrache,

Micheau

2024

Cells

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TNF-related apoptosis-inducing ligand (TRAIL or Apo2 or TNFSF10) belongs to the TNF superfamily. When bound to its agonistic receptors, TRAIL can induce apoptosis in tumour cells, while sparing healthy cells. Over the last three decades, this tumour selectivity has prompted many studies aiming at evaluating the anti-tumoral potential of TRAIL or its derivatives. Although most of these attempts have failed, so far, novel formulations are still being evaluated. However, emerging evidence indicates that TRAIL can also trigger a non-canonical signal transduction pathway that is likely to be detrimental for its use in oncology. Likewise, an increasing number of studies suggest that in some circumstances TRAIL can induce, via Death receptor 5 (DR5), tumour cell motility, potentially leading to and contributing to tumour metastasis. While the pro-apoptotic signal transduction machinery of TRAIL is well known from a mechanistic point of view, that of the non-canonical pathway is less understood. In this study, we the current state of knowledge of TRAIL non-canonical signalling.

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Section: The Trail Systemmentioning

confidence: 99%

TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling

Guerrache,

Micheau

2024

Cells

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“…However, the ectodomain and ICD are separated by the TMD, which may also contribute to driving a signaling-compatible configuration. The preligand conformation of receptor ectodomains could physically prevent ligand-independent, TMD-driven signaling ( 14 , 20 ). To test whether heterotypic association between the ILR TMD and the γc TMD can be achieved by the removal of ectodomains, wild-type (WT) or cleavable human IL-7R (hIL-7R) and γc were designed (Fig.…”

Section: Removal Of An Ilr (Il-7r or Il-9r) And γC Ectodomains Activa...mentioning

confidence: 99%

Structural basis of γ chain family receptor sharing at the membrane level

Cai,

Lenoir Capello,

et al. 2023

Science

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Common γ chain (γc) cytokine receptors, including interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21 receptors, are activated upon engagement with a common γc receptor (CD132) by concomitant binding of their ectodomains to an interleukin. In this work, we find that direct interactions between the transmembrane domains (TMDs) of both the γc and the interleukin receptors (ILRs) are also required for receptor activation. Moreover, the same γc TMD can specifically recognize multiple ILR TMDs of diverse sequences within the family. Heterodimer structures of γc TMD bound to IL-7 and IL-9 receptor TMDs—determined in a lipid bilayer–like environment by nuclear magnetic resonance spectroscopy—reveal a conserved knob-into-hole mechanism of recognition that mediates receptor sharing within the membrane. Thus, signaling in the γc receptor family requires specific heterotypic interactions of the TMDs.

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“…However, the clustering mechanisms for both DR5 and Fas remained elusive until recently. Using clinical bivalent or multivalent monospecific antibodies, bispecific antibodies, receptor mutagenesis studies, functional assays, and NMR structure analysis of DR5, a series of papers have discovered and characterized receptor clustering conformation autoinhibitory motifs in the DR5 extracellular domain (ECD) [3,4]. The key described motif comprises a cysteine-stabilized patch of positively charged (arginine, lysine) amino acid residues in DR5 CRD3.…”

Section: Introductionmentioning

confidence: 99%

Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer

Mondal,

Gaur,

Wamba

et al. 2023

Cell Death Differ

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Receptor clustering is the most critical step to activate extrinsic apoptosis by death receptors belonging to the TNF superfamily. Although clinically unsuccessful, using agonist antibodies, the death receptors-5 remains extensively studied from a cancer therapeutics perspective. However, despite its regulatory role and elevated function in ovarian and other solid tumors, another tumor-enriched death receptor called Fas (CD95) remained undervalued in cancer immunotherapy until recently, when its role in off-target tumor killing by CAR-T therapies was imperative. By comprehensively analyzing structure studies in the context of the binding epitope of FasL and various preclinical Fas agonist antibodies, we characterize a highly significant patch of positively charged residue epitope (PPCR) in its cysteine-rich domain 2 of Fas. PPCR engagement is indispensable for superior Fas agonist signaling and CAR-T bystander function in ovarian tumor models. A single-point mutation in FasL or Fas that interferes with the PPCR engagement inhibited apoptotic signaling in tumor cells and T cells. Furthermore, considering that clinical and immunological features of the autoimmune lymphoproliferative syndrome (ALPS) are directly attributed to homozygous mutations in FasL, we reveal differential mechanistic details of FasL/Fas clustering at the PPCR interface compared to described ALPS mutations. As Fas-mediated bystander killing remains vital to the success of CAR-T therapies in tumors, our findings highlight the therapeutic analytical design for potentially effective Fas-targeting strategies using death agonism to improve cancer immunotherapy in ovarian and other solid tumors.

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Autoinhibitory structure of preligand association state implicates a new strategy to attain effective DR5 receptor activation

Cited by 6 publications

References 66 publications

TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling

TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling

Structural basis of γ chain family receptor sharing at the membrane level

Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer

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