ILDR2

ILDR2 is a type I transmembrane immunoglobulin-superfamily protein with context-dependent roles spanning tricellular junction organization, immune tolerance, and pre-mRNA splicing (PMID:23239027, PMID:29431694, PMID:28785060). As an angulin family member alongside LSR and ILDR1, it localizes to tricellular contacts in epithelia and recruits tricellulin to tricellular tight junctions, although it confers only weak barrier function relative to its paralogs (PMID:23239027). In the kidney, ILDR2 (angulin-3) marks tricellular and then bicellular junctions across podocyte development and injury, interacts with claudin-5 (CLDN5), and its genetic loss produces glomerular hypertrophy, reduced podocyte density, and accumulation of matrix proteins, consistent with a protective role in glomerulopathies (PMID:38311119, PMID:39640577). Beyond junctions, ILDR2 acts as a negative regulator of T cell responses: an ILDR2 extracellular domain–Fc fusion binds a counterpart on activated T cells and suppresses proinflammatory cytokine production, and ILDR2 on CD206hi macrophages drives TGF-β-dependent induction of Foxp3+ regulatory T cells, supporting antigen-specific immune tolerance (PMID:29431694, PMID:39626366). ILDR2 also binds the splicing factors TRA2A, TRA2B, and SRSF1, translocates to the nucleus in their presence, and regulates alternative splicing of TUBD1 and IQCB1 (PMID:28785060). Rigorous liver- and hepatocyte-specific knockouts establish that ILDR2 plays a negligible direct role in hepatic steatosis, with earlier shRNA phenotypes attributable to off-target effects on Dgka (PMID:29847571).

1. 2012 High

   Established ILDR2 as an angulin-family tricellular junction protein, defining its first molecular role in epithelial junction architecture.

   Evidence Immunofluorescence localization and functional tricellulin recruitment assays in mouse epithelial tissues and cultured cells

   PMID:23239027

   Open questions at the time

   • Weak barrier function relative to LSR/ILDR1 left its physiological junction role unclear
   • No structural basis for tricellulin recruitment defined
2. 2013 Medium

   Localized ILDR2 to the ER membrane and linked hepatic ILDR2 manipulation to lipid homeostasis and ER stress, a claim later overturned at the gene level.

   Evidence Subcellular fractionation in cell lines plus adenoviral shRNA knockdown and overexpression in mouse liver with lipid and ER-stress readouts

   PMID:23826244

   Open questions at the time

   • Causal primacy between lipid and ER-stress effects unresolved
   • Effects later attributed to shRNA off-target action on Dgka
3. 2017 Medium

   Revealed a nuclear, RNA-regulatory function by showing ILDR2 binds splicing factors and controls alternative splicing, distinct from its junctional role.

   Evidence Co-IP/pulldown with TRA2A/TRA2B/SRSF1, nuclear translocation assay, and siRNA knockdown with RT-PCR splicing readouts

   PMID:28785060

   Open questions at the time

   • Mechanism coupling a transmembrane protein to nuclear splicing unclear
   • Limited to two splicing targets in one lab
4. 2018 Medium

   Defined ILDR2 as a B7-like negative immune regulator, identifying a new immunological function with therapeutic relevance.

   Evidence ILDR2-Fc binding assay on activated T cells, macrophage–T cell coculture cytokine assays, and collagen-induced arthritis model

   PMID:29431694

   Open questions at the time

   • T cell counter-receptor identity undefined
   • Single lab
5. 2018 High

   Disproved the prior hepatic steatosis model by genetic knockout, showing earlier shRNA phenotypes were off-target.

   Evidence Liver- and hepatocyte-specific Cre knockouts, shRNA rescue in knockout background, and RNA-seq/BLAST identifying Dgka as the off-target

   PMID:29847571

   Open questions at the time

   • Does not address non-hepatic metabolic roles
6. 2021 Medium

   Identified ER chaperone partners that stabilize ILDR2 and linked it to β-cell insulin secretion.

   Evidence TAP-tag MS, Co-IP validation of GRP78/PDIA1 interaction, proteasome inhibitor stabilization assay, and knockdown with glucose-stimulated insulin secretion in MIN6 cells

   PMID:33863978

   Open questions at the time

   • Mechanism linking ILDR2 stability to insulin secretion undefined
   • Single lab
7. 2024 Medium

   Extended the immune-tolerance role by showing macrophage ILDR2 drives Treg induction via TGF-β.

   Evidence Coculture of CD206hiILDR2+ macrophages with naïve CD4+ T cells, anti-TGF-β blockade, and RNA-seq of macrophage subsets

   PMID:39626366

   Open questions at the time

   • Receptor-level mechanism on T cells not defined
   • In vitro only
8. 2024 Medium

   Established a podocyte-protective junctional role through CLDN5 interaction and knockout glomerular phenotype.

   Evidence Co-IP with CLDN5, Ildr2 knockout phenotyping, glomerular LC-MS/MS proteomics, scRNA-seq, and superresolution imaging across development and injury

   PMID:38311119 PMID:39640577

   Open questions at the time

   • Functional consequence of junctional relocalization in injury unresolved
   • Causal chain from CLDN5 binding to matrix accumulation not established

• How a single transmembrane protein integrates junctional, nuclear-splicing, ER-chaperone, and immune-checkpoint activities, and the identity of its T cell counter-receptor, remain unresolved.
• No unifying mechanism connecting the distinct functional contexts
• T cell receptor partner unidentified
• No structural model