RELL1

RELL1 is a plasma membrane-associated member of the RELT family of TNF receptor superfamily homologues that functions as a signaling and apoptosis-inducing adaptor (PMID:16389068, PMID:19969290). Through its intracellular domain it nucleates a multiprotein complex, physically interacting with RELT and RELL2, with the kinase OSR1/OXSR1 (which phosphorylates RELL1 in vitro), with phospholipid scramblase PLSCR1, and with the hematopoietic factor MDFIC, several of which co-localize with RELL1 at the plasma membrane (PMID:16389068, PMID:22052202, PMID:33367115). Functionally, RELL1 overexpression activates the p38 MAPK pathway through OSR1 and TRAF2 and induces apoptosis, although the cell-death activity does not depend on OSR1/OXSR1-mediated phosphorylation (PMID:28688764, PMID:39767574). In macrophages, RELL1 directly interacts with mTOR to enhance mTOR activity and suppress autophagy flux, increasing proinflammatory cytokine output and promoting intracellular Mycobacterium tuberculosis survival (PMID:32090861).

1. 2005 High

   Established RELL1 as a RELT-family membrane protein and identified its first binding partners and a candidate regulatory kinase, defining a starting framework for its signaling role.

   Evidence Yeast two-hybrid with the RELL1 intracellular domain, in vitro Co-IP, in vitro kinase assay, and co-localization imaging

   PMID:16389068

   Open questions at the time

   • Functional consequence of OSR1 phosphorylation of RELL1 not defined
   • Interactions shown in vitro/overexpression, not at endogenous levels
2. 2009 Medium

   Showed RELL1 has a cellular output by demonstrating that its overexpression triggers apoptosis, linking the receptor-like protein to programmed cell death.

   Evidence Transient overexpression in HEK 293 cells with morphological scoring and DNA fragmentation assay

   PMID:19969290

   Open questions at the time

   • Apoptotic pathway and effector caspases not mapped
   • Overexpression phenotype not validated by endogenous loss-of-function
3. 2011 High

   Extended the interaction network to PLSCR1 and provided evidence for a functional RELT-OSR1-PLSCR1 complex, suggesting RELL1 assembles substrate-presenting modules at the membrane.

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

   PMID:22052202

   Open questions at the time

   • Whether OSR1 phosphorylates PLSCR1 in a RELL1-dependent (versus RELT-dependent) manner not resolved
   • Downstream consequence of PLSCR1 modification unknown
4. 2017 Medium

   Placed RELL1 upstream of a defined signaling cascade by showing its activation of p38 MAPK requires OSR1 and TRAF2, distinguishing RELL1 signaling potency from RELT.

   Evidence Overexpression with dominant-negative OSR1/TRAF2 epistasis and western blotting for p38 phosphorylation in HEK-293 cells

   PMID:28688764

   Open questions at the time

   • Endogenous physiological trigger for p38 activation unknown
   • Dominant-negative epistasis does not establish direct enzymatic order
5. 2020 Medium

   Revealed an immune/metabolic role distinct from membrane signaling, showing RELL1 directly binds mTOR to suppress autophagy and favor intracellular bacterial persistence in macrophages.

   Evidence RAW264.7 macrophage overexpression, cytokine ELISA, autophagy flux assays, and Co-IP for mTOR interaction

   PMID:32090861

   Open questions at the time

   • How a membrane protein engages mTOR mechanistically not defined
   • Single cell model and single lab
6. 2020 Medium

   Added MDFIC to the RELL1 interactome, expanding partners to a hematopoietic transcription factor at the plasma membrane.

   Evidence Yeast two-hybrid, Co-IP with deletion mapping, and co-localization imaging

   PMID:33367115

   Open questions at the time

   • Functional consequence of the RELL1-MDFIC interaction unknown
   • Interaction not validated at endogenous levels
7. 2024 Medium

   Dissociated RELT-family apoptosis from OSR1/OXSR1-mediated p38 signaling, showing phosphorylation-blocking does not abrogate cell death and revealing a nuclear pool of RELT.

   Evidence Phosphorylation-blocking mutant co-transfection, Co-IP, immunofluorescence, and flow cytometry for caspase-3/7 and phosphatidylserine externalization in MDA-MB-231 cells

   PMID:39767574

   Open questions at the time

   • The phosphorylation-independent apoptotic mechanism is not identified
   • Findings centered on RELT; direct RELL1 generalization not fully tested

• The endogenous physiological ligand/trigger of RELL1 and the molecular basis distinguishing its pro-apoptotic, p38-activating, and mTOR-regulatory functions remain unresolved.
• No defined extracellular ligand or activation signal
• Phosphorylation-independent apoptotic effector unknown
• Mechanism linking a membrane protein to mTOR/autophagy not established