LRRC25

LRRC25 is a type I transmembrane leucine-rich repeat protein expressed predominantly in myeloid cells that acts as a broad negative regulator of innate immune signaling by coupling immune effectors to selective autophagic degradation (PMID:29288164, PMID:28536942). In antiviral signaling, LRRC25 binds ISG15-conjugated RIG-I and bridges it to the autophagic cargo receptor p62, driving selective autophagic turnover of RIG-I and dampening type I IFN responses; loss of either LRRC25 or ISG15 abolishes the RIG-I–p62 interaction (PMID:29288164). The same degradative logic applies to NF-κB signaling, where the LRR domain of LRRC25 directly engages the Rel Homology domain of p65/RelA and enhances its p62-dependent autophagic degradation, so that LRRC25 loss potentiates NF-κB activation and inflammatory cytokine output (PMID:29044191). Picornaviruses exploit this axis: viral 3A proteins acting through G3BP1 upregulate LRRC25, which then degrades G3BP1 to suppress RIG-I/MDA5 signaling and IFN induction (PMID:31996428). Beyond pathogen sensing, LRRC25 is required for ATRA-induced terminal granulocytic differentiation (PMID:28536942), restrains anti-tuberculosis IFN-γ secretion and free ISG15 in microglia (PMID:37894158), and shapes tumor-associated macrophage programming, with its deficiency activating a Nox2-ROS-Nlrp3-IL1β axis that promotes anti-tumor immunity (PMID:40279244). In vivo, LRRC25 loss aggravates pathological cardiac hypertrophy through enhanced TGF-β1/Smad2/3 and NF-κB signaling (PMID:30340835).

1. 2017 High

   Established LRRC25 as a selective autophagy adaptor that terminates antiviral signaling by linking ISG15-modified RIG-I to p62 for degradation, answering how RIG-I is cleared to limit type I IFN.

   Evidence Reciprocal Co-IP, knockdown/knockout of LRRC25 and ISG15, autophagic flux assays in RNA virus infection models

   PMID:29288164

   Open questions at the time

   • Structural basis of ISG15-RIG-I recognition by LRRC25 not resolved
   • Whether membrane anchoring is required for the bridging function untested
2. 2017 High

   Showed the same LRRC25-p62 degradative mechanism operates on NF-κB, with the LRR domain directly binding the p65/RelA RHD, defining a shared logic across two innate pathways.

   Evidence Domain-mapping Co-IP (LRR vs RHD), CRISPR/Cas9 knockout, autophagic degradation and cytokine assays

   PMID:29044191

   Open questions at the time

   • Direct LRR-RHD binding not validated by purified-protein reconstitution
   • Selectivity for p65 over other Rel-family members not addressed
3. 2017 High

   Identified a developmental role distinct from immune suppression, showing LRRC25 is required for ATRA-induced granulocytic differentiation in myeloid cells.

   Evidence siRNA/shRNA knockdown, CRISPR-KO with rescue, flow cytometry for differentiation markers

   PMID:28536942

   Open questions at the time

   • Molecular link between LRRC25 and the ATRA differentiation program unknown
   • Whether the autophagy adaptor function underlies differentiation untested
4. 2018 Medium

   Extended LRRC25 function to cardiac pathology, showing its loss accelerates hypertrophy via TGF-β1/Smad2/3 and NF-κB, consistent with its role as a brake on inflammatory signaling.

   Evidence LRRC25 knockout mouse, aortic banding and angiotensin II models, phospho-Smad2/3 blots, pathway inhibitor rescue

   PMID:30340835

   Open questions at the time

   • Direct binding partners in the TGF-β1/Smad pathway not mapped
   • Cell type driving the cardiac phenotype not defined
5. 2020 Medium

   Revealed that picornaviruses co-opt LRRC25, with viral 3A proteins inducing it to degrade G3BP1 and suppress RLH signaling, expanding its substrate repertoire and showing pathogen exploitation.

   Evidence Co-IP, viral 3A overexpression, siRNA knockdown, IFN reporter assays across multiple picornaviruses

   PMID:31996428

   Open questions at the time

   • Whether G3BP1 degradation uses the same p62-autophagy route as RIG-I not directly shown
   • Mechanism of 3A-driven LRRC25 upregulation unresolved
6. 2023 Medium

   Demonstrated LRRC25 restrains anti-tuberculosis immunity in microglia by suppressing IFN-γ secretion and degrading free ISG15, extending its immunosuppressive role to CNS-resident myeloid cells.

   Evidence siRNA knockdown in BV2 microglia, H37Rv infection, ELISA for IFN-γ and ISG15

   PMID:37894158

   Open questions at the time

   • Single loss-of-function method per endpoint without rescue
   • Direct mechanism connecting LRRC25 to IFN-γ control not defined
7. 2025 Medium

   Showed LRRC25 deficiency reprograms tumor-associated macrophages toward anti-tumor activity via a Nox2-ROS-Nlrp3-IL1β axis, linking its myeloid expression to tumor immune control.

   Evidence Lrrc25-deficient mice, multiple murine tumor models, TAM phenotyping, CD8+ T cell flow cytometry

   PMID:40279244

   Open questions at the time

   • Direct molecular target of LRRC25 within the Nox2-Nlrp3 axis not identified
   • Whether autophagy adaptor activity drives TAM reprogramming untested
8. 2024 Low

   Characterized LRRC25 subcellular distribution and age/region-dependent brain expression, with elevation in Alzheimer's disease models and patient tissue, raising an associative CNS link.

   Evidence Immunoblot, immunofluorescence, subcellular fractionation in cell lines and mouse brain, AD model and human tissue comparison

   PMID:38476461

   Open questions at the time

   • Associative expression change without demonstrated functional consequence in AD
   • No causal manipulation of LRRC25 in neurodegeneration models

• How LRRC25 selects its diverse substrates (RIG-I, p65, G3BP1) and whether its transmembrane anchoring and a unifying biochemical activity govern adaptor specificity remains unresolved.
• No structure of LRRC25 or its substrate complexes
• Determinants of substrate selectivity across pathways unknown
• Role of membrane topology in adaptor function undefined