RELT

RELT is a type I transmembrane TNF receptor superfamily member with a cysteine-rich extracellular domain that couples to the Ste20-related kinases SPAK and OSR1 to drive stress-MAPK signaling and apoptosis (PMID:11313261, PMID:16530727, PMID:16389068). RELT binds SPAK through a 349RFRV motif in its intracellular domain to activate p38 and JNK, and disrupting this motif or using kinase-dead SPAK abolishes the response (PMID:16530727); OSR1 binds and phosphorylates RELT and its homologues RELL1/RELL2, and assembles with RELT and the substrate PLSCR1 into a membrane-associated multiprotein complex (PMID:16389068, PMID:22052202). RELT overexpression induces apoptosis in a cell-type-dependent manner through a FADD/Caspase-8-independent route that requires the full intracellular domain and does not depend on OXSR1-mediated phosphorylation (PMID:19969290, PMID:28688764, PMID:39767574). The receptor is regulated by ADAM10-mediated ectodomain shedding (PMID:31575895) and additionally interacts with TRAF1 and MDFIC (PMID:11313261, PMID:33367115). Physiologically, RELT negatively regulates the early phase of T-cell activation in vivo, restraining CD4+ homeostatic proliferation and CD8+ anti-tumor responses (PMID:30138536). Loss-of-function mutations in RELT cause autosomal recessive amelogenesis imperfecta, and RELT is expressed by secretory-stage ameloblasts and odontoblasts where it is required for normal enamel formation (PMID:30506946).

1. 2001 Medium

   Establishing RELT as a TNFRSF member, the first study showed it engaged NF-κB signaling, bound TRAF1 selectively, and costimulated T cells, framing it as an immune-regulatory receptor.

   Evidence Cloning, NF-κB reporter, co-IP binding assay, and mixed lymphocyte reaction in transfected cells

   PMID:11313261

   Open questions at the time

   • NF-κB activation not reproduced in later work
   • endogenous ligand unidentified
   • physiological TRAF1 dependence untested
2. 2005 High

   Identifying OSR1 as a binding kinase that phosphorylates RELT, RELL1, and RELL2 defined the RELT family as substrates of a Ste20-related kinase at the plasma membrane.

   Evidence Yeast two-hybrid, co-IP, co-localization microscopy, and in vitro kinase assay

   PMID:16389068

   Open questions at the time

   • functional consequence of OSR1 phosphorylation undefined
   • phosphorylation sites not mapped
3. 2006 High

   Mapping the 349RFRV motif that recruits SPAK and showing it is required for p38/JNK activation pinpointed the structural determinant linking RELT to stress-MAPK signaling, while contradicting the earlier NF-κB/TRAF model.

   Evidence Yeast two-hybrid, co-IP, motif mutagenesis, dominant-negative kinase, and MAPK/NF-κB reporter assays in 293 cells

   PMID:16530727

   Open questions at the time

   • discrepancy with 2001 NF-κB/TRAF1 findings unresolved
   • all data from overexpression
   • no endogenous-level validation
4. 2009 Medium

   Demonstrating that RELT overexpression triggers apoptosis with cell-type-dependent outcomes established RELT as a death-inducing receptor.

   Evidence Transient overexpression with morphology and DNA-fragmentation assays in HEK-293 and COS-7 cells

   PMID:19969290

   Open questions at the time

   • apoptotic pathway not defined
   • overexpression-only evidence
   • no link to physiological signaling
5. 2011 Medium

   Showing OSR1 phosphorylates PLSCR1 only in the presence of RELT defined a functional RELT–OSR1–PLSCR1 complex, connecting the receptor to a phospholipid scramblase substrate.

   Evidence Yeast two-hybrid, co-IP, immunofluorescence, and RELT-dependent in vitro kinase assay

   PMID:22052202

   Open questions at the time

   • downstream effect of PLSCR1 phosphorylation unknown
   • complex not validated endogenously
6. 2017 Medium

   Defining RELT-induced apoptosis as FADD/Caspase-8-independent and requiring the full intracellular domain distinguished RELT from classical death-domain TNFRs and implicated OSR1/TRAF2 in its MAPK output.

   Evidence Deletion mutagenesis, OSR1/TRAF2 dominant-negatives, FADD/Caspase-8 blockade, MAPK and apoptosis assays in HEK-293

   PMID:28688764

   Open questions at the time

   • the putative C-terminal death domain not structurally confirmed
   • effector caspases not identified
   • overexpression-based
7. 2018 Medium

   A RELT knockout mouse revealed RELT as an in vivo negative regulator of early T-cell activation, providing the first physiological role linked to its apoptotic activity.

   Evidence RELT-/- mice, adoptive transfer, in vivo tumor model, T-cell proliferation/response assays

   PMID:30138536

   Open questions at the time

   • molecular pathway in T cells not delineated
   • ligand and upstream activation signal unknown
8. 2018 High

   Human loss-of-function mutations plus CRISPR KO mice established RELT as causative for autosomal recessive amelogenesis imperfacta, assigning it an unexpected role in enamel biology.

   Evidence Homozygosity mapping/sequencing, CRISPR/Cas9 mice, RNAscope, micro-CT/histology

   PMID:30506946

   Open questions at the time

   • signaling mechanism in ameloblasts undefined
   • link between MAPK/apoptosis activity and enamel formation unestablished
9. 2019 Medium

   Identifying ADAM10 as the specific sheddase of the RELT ectodomain in ameloblasts introduced post-translational regulation of RELT during enamel development.

   Evidence ADAM expression PCR in enamel organs and ADAM10-vs-ADAM17 proteolytic cleavage assay

   PMID:31575895

   Open questions at the time

   • functional consequence of shedding for signaling not shown
   • fate of shed fragments unknown
10. 2020 Medium

    Mapping a physical MDFIC–RELT interaction added a new membrane-associated binding partner to the RELT family interactome.

    Evidence Yeast two-hybrid, co-IP with deletion mapping, immunofluorescence co-localization

    PMID:33367115

    Open questions at the time

    • functional role of MDFIC binding unknown
    • single-lab interaction
11. 2024 Medium

    Detecting nuclear RELT and confirming OXSR1-phosphorylation-independent apoptosis in breast cancer cells extended RELT's death activity beyond immune cells and decoupled it from OSR1 phosphorylation.

    Evidence Nuclear fractionation/western, immunofluorescence, flow cytometry (PS, Caspase-3/7), co-IP with OXSR1-binding mutant in MDA-MB-231 and HEK-293

    PMID:39767574

    Open questions at the time

    • function of nuclear RELT undefined
    • mechanism of nuclear translocation unknown
12. 2024 Medium

    Placing secreted RELT downstream of LILRB4 in myeloma-driven osteoclastogenesis linked RELT to bone pathology via a p-SHP2/NF-κB axis.

    Evidence LILRB4 KO, conditioned medium, cytokine array, co-IP, luciferase reporter, xenograft/PDX models, micro-CT

    PMID:38951916

    Open questions at the time

    • receptor mediating secreted RELT's osteoclast effect unidentified
    • relationship to ADAM10 shedding unclear

• How RELT's SPAK/OSR1-coupled MAPK signaling, its caspase-independent apoptotic activity, and its tissue roles in enamel formation, T-cell regulation, and bone remodeling are mechanistically unified — and what its physiological ligand is — remains unresolved.
• no identified endogenous ligand
• C-terminal death domain unconfirmed structurally
• mechanism connecting receptor signaling to enamel biology unknown