ILRUN

ILRUN (C6orf106) is a multifunctional regulator that restrains innate immune transcription and shapes lipid metabolism through its capacity to bind ubiquitinylated proteins and limit transcriptional coactivator availability (PMID:29802199, PMID:32912065). In antiviral signaling, ILRUN interacts with IRF3 and blocks its recruitment to type I interferon promoters without altering IRF3 activation or nuclear translocation, instead reducing nuclear levels of the coactivators CBP and p300 by inducing their degradation, thereby suppressing IFN-α/β and TNF-α transcription (PMID:29802199, PMID:37031606). Both a UBA-like domain and an NBR1-like domain are required for this cytokine-suppressive activity, and the UBA-like domain mediates binding to ubiquitinylated substrates including PPARα (PMID:32518853, PMID:32912065). ILRUN-deficient mice confirm these roles in vivo: loss of ILRUN elevates inflammatory cytokine output from splenocytes and alters T cell subset populations (PMID:37031606), while in the liver ILRUN deficiency raises PPARα protein and lowers hepatic lipoprotein production and plasma cholesterol (PMID:32912065). ILRUN promotes atherogenesis through both lipid-dependent and lipid-independent routes, the latter including suppression of macrophage MerTK expression and efferocytosis (PMID:35861973). ILRUN additionally functions as a negative regulator of SARS-CoV-2 entry factors, downregulating ACE2, TMPRSS2, and CTSL to limit viral replication (PMID:33963054), and influences cancer cell invasion and proliferation in part through ERK signaling (PMID:30311108).

1. 2015 Medium

   Before any immune or metabolic role was known, ILRUN was first linked to tumor cell behavior, establishing that it influences proliferation, invasion, and epithelial-mesenchymal transition.

   Evidence siRNA knockdown and overexpression in breast and lung cancer lines with proliferation, invasion, and EMT marker readouts

   PMID:25736925 PMID:25953261

   Open questions at the time

   • No molecular mechanism connecting ILRUN to EMT markers identified
   • Cell-line phenotypes not validated in vivo
   • Direct binding partners not defined
2. 2018 High

   The core innate immune function was defined: ILRUN suppresses interferon and TNF-α transcription not by blocking IRF3/NF-κB activation but by impairing IRF3 promoter recruitment and depleting nuclear CBP/p300.

   Evidence Overexpression/knockdown, reporter assays, Co-IP, and ChIP in human cells stimulated with poly(I:C) and Sendai virus

   PMID:29802199

   Open questions at the time

   • Mechanism by which coactivator nuclear levels are reduced not yet defined
   • Whether IRF3 binding is direct not structurally confirmed
3. 2018 Medium

   A pro-tumorigenic signaling axis was placed upstream of ERK, showing ILRUN can act through a defined kinase pathway in pancreatic cancer.

   Evidence Overexpression/knockdown plus pharmacological ERK inhibition (PD98059) with invasion, proliferation, and Western blot readouts

   PMID:30311108

   Open questions at the time

   • How ILRUN engages ERK signaling mechanistically unknown
   • Relationship to the immune/coactivator function not addressed
4. 2020 High

   The structural basis of ILRUN function was established by identifying two essential domains, defining it as a ubiquitin-binding adaptor.

   Evidence Domain deletion/mutation cytokine transcription assays and X-ray crystallography of the NBR1-like domain

   PMID:32518853

   Open questions at the time

   • No full-length structure
   • Ubiquitin-binding specificity of the UBA-like domain not characterized at this stage
5. 2020 High

   A metabolic role was uncovered, linking ILRUN to hepatic lipoprotein production via UBA-domain-dependent binding of ubiquitinylated PPARα.

   Evidence Global Ilrun KO mice with plasma lipid and liver transcriptome analysis plus Co-IP of ILRUN with ubiquitinylated PPARα using UBA-domain mutants

   PMID:32912065

   Open questions at the time

   • Whether ILRUN directs PPARα degradation not shown
   • Connection between ubiquitin-binding and coactivator regulation not unified
6. 2021 Medium

   ILRUN was identified as an antiviral factor against SARS-CoV-2 by transcriptionally downregulating viral entry machinery.

   Evidence Knockdown/overexpression in Caco-2 cells with RNA-seq and SARS-CoV-2 replication assays

   PMID:33963054

   Open questions at the time

   • Mechanism of ACE2/TMPRSS2/CTSL repression not defined
   • Not validated in vivo or in primary airway cells
7. 2022 High

   ILRUN was shown to promote atherosclerosis through both lipid-dependent and lipid-independent mechanisms, the latter via suppression of macrophage efferocytosis.

   Evidence Ilrun KO on hyperlipidemic backgrounds with hepatic-specific reconstitution, lesion quantification, MerTK expression, and efferocytosis assays

   PMID:35861973

   Open questions at the time

   • How ILRUN regulates MerTK expression unknown
   • Direct molecular link between hepatic and macrophage functions not established
8. 2023 High

   In vivo loss-of-function confirmed the immunosuppressive mechanism and extended it to T cell development.

   Evidence ILRUN knockout mouse with splenocyte cytokine assays, CBP/p300 degradation analysis, and flow cytometry of immune subsets

   PMID:37031606

   Open questions at the time

   • Cell-intrinsic versus systemic basis of T cell subset changes not resolved
   • Mechanism of CBP/p300 degradation still undefined

• The unifying biochemical mechanism linking ILRUN's ubiquitin-binding activity to coactivator degradation, PPARα regulation, and entry-factor repression remains unresolved.
• Whether ILRUN is an adaptor for an E3 ligase or degradation machinery is unknown
• No structure of ILRUN bound to ubiquitin or substrates
• How a single ubiquitin-binding adaptor coordinates immune, metabolic, and viral functions is unexplained