LACC1

LACC1 (FAMIN) is a multifunctional immunometabolic enzyme that couples central metabolism to innate immune effector functions in macrophages (PMID:27478939, PMID:31978345). Biochemically, it is a promiscuous purine enzyme that phosphorolytically cleaves adenosine and carries adenosine deaminase, purine nucleoside phosphorylase, and methylthioadenosine phosphorylase activities, enabling a purine nucleotide cycle that consumes aspartate and releases fumarate to synchronize mitochondrial activity with glycolysis through fatty-acid oxidation (PMID:31978345); it additionally converts L-citrulline to L-ornithine, bridging NOS2-driven inflammation to ODC1-dependent polyamine metabolism (PMID:35978195). Through complex formation with fatty acid synthase on peroxisomes, LACC1 promotes de novo lipogenesis that fuels FAO and ATP regeneration, thereby controlling inflammasome activation, mitochondrial and NADPH-oxidase ROS, and bactericidal capacity (PMID:27478939, PMID:27959965). In innate immune signaling, LACC1 is recruited to the NOD2-signalling complex and constitutively associates with succinate dehydrogenase subunit A to amplify PRR-induced SDH activity, mitochondrial ROS, cytokine secretion and bacterial clearance (PMID:28593945), and upon NOD2 stimulation relocalizes to the ER where it engages the PERK/IRE1α/ATF6 stress sensors required for antimicrobial output (PMID:31875558). LACC1 expression is induced via mTOR and its turnover is autophagy-dependent, with RACK1 and AMPK as interaction partners supporting autophagy flux and macrophage bioenergetics (PMID:33606008). Myeloid LACC1 is required in vivo for control of intestinal bacterial burden and for balanced Th1/Th17 versus Th2 responses (PMID:32693188). Disease-risk variants p.I254V and p.C284R cause diminished or lost function across these activities (PMID:27478939, PMID:31875558).

1. 2016 High

   Established the first molecular function of LACC1/FAMIN by showing it acts as a metabolic hub on peroxisomes that links lipid metabolism to macrophage antimicrobial effector functions, explaining how a disease-risk locus shapes immunity.

   Evidence Co-IP with FASN, metabolic flux assays, and macrophage knockout/knockdown with ROS, inflammasome, bacterial-killing and endotoxin-shock readouts; immunofluorescence localization to peroxisomes

   PMID:27478939 PMID:27959965

   Open questions at the time

   • The direct enzymatic activity of LACC1 itself was not defined
   • How the FASN complex is assembled or regulated was not established
2. 2017 High

   Connected LACC1 to a defined innate-immune receptor pathway, showing it physically joins the NOD2 signalling complex and boosts mitochondrial respiratory output to amplify antimicrobial responses.

   Evidence Reciprocal Co-IP of LACC1 with the NOD2 complex and SDH subunit A, siRNA knockdown, disease-variant transfection, mitochondrial ROS and bacterial clearance assays in human macrophages

   PMID:28593945

   Open questions at the time

   • Whether LACC1 directly modifies SDH or acts indirectly was not resolved
   • Mechanism of recruitment to the NOD2 complex unknown
3. 2019 High

   Added a subcellular dimension to NOD2 signalling by showing stimulation drives LACC1 to the ER where it cooperates with all three unfolded-protein-response branches to enable antimicrobial output.

   Evidence Immunofluorescence localization, Co-IP of LACC1 with ER-stress sensors, siRNA knockdown of PERK/IRE1α/ATF6, disease-variant rescue by ER-stress restoration in macrophages

   PMID:31875558

   Open questions at the time

   • How LACC1 traffics between peroxisomes, mitochondria and ER was not defined
   • Direct biochemical link between LACC1 enzymatic activity and ER-stress sensor engagement unestablished
4. 2020 High

   Defined the long-sought catalytic identity of LACC1 as a multifunctional purine enzyme, revealing an unprecedented adenosine phosphorolysis activity that powers a purine nucleotide cycle coordinating mitochondrial and glycolytic metabolism.

   Evidence Unbiased LC-MS enzymatic activity screen with purified protein, in vitro reconstitution of multiple activities, and macrophage metabolic studies

   PMID:31978345

   Open questions at the time

   • No structural basis for the multiple activities reported
   • Relative physiological contribution of each catalytic activity not weighted
5. 2020 High

   Demonstrated the cell-autonomous, myeloid requirement for LACC1 in vivo, linking its loss to defective bacterial handling and skewed adaptive T-cell responses through PDK1-dependent uptake and MAPK/NF-κB-driven effector programs.

   Evidence Lacc1Δmye conditional knockout mice, T-cell transfer and DSS colitis, oral Salmonella infection, and BMDM assays for ROS, RNS, autophagy and bacterial uptake with cytokine complementation

   PMID:32693188

   Open questions at the time

   • Whether enzymatic activities identified in vitro drive each in vivo phenotype not directly tested
   • Molecular link between LACC1 and PDK1 not defined
6. 2021 Medium

   Placed LACC1 in the autophagy network, identifying RACK1 and AMPK as partners and showing autophagy controls LACC1 stability while LACC1-supported autophagy fuels macrophage bioenergetics.

   Evidence Bimolecular fluorescence complementation and biochemical assays for RACK1/AMPK interaction, autophagy-flux, lipid-droplet and mitochondrial-respiration readouts in patient-derived macrophages

   PMID:33606008

   Open questions at the time

   • Interactions shown in a single lab without reciprocal validation in independent systems
   • Directionality between autophagy regulation and LACC1 enzymatic function unresolved
7. 2022 High

   Identified a second discrete enzymatic activity, citrulline-to-ornithine conversion, biochemically and genetically positioning LACC1 between NOS2 and polyamine biosynthesis as the basis of its antimicrobial phenotypes.

   Evidence Biochemical enzyme assays, Lacc1-/- mice, NOS2/ODC1 genetic epistasis, L-ornithine chemical complementation, and Salmonella infection

   PMID:35978195

   Open questions at the time

   • How this activity integrates with the purine nucleotide cycle in the same enzyme not addressed
   • Isocyanic acid fate and downstream signaling not characterized
8. 2022 Low

   Extended LACC1's inflammatory role to ischemic injury, placing it upstream of AMPK/NLRP3 in macrophage oxidative-stress and inflammatory signaling.

   Evidence siRNA knockdown with AMPK-inhibitor rescue, ROS and cytokine measurement in an in vitro stroke model

   PMID:35833820

   Open questions at the time

   • Single lab with limited mechanistic detail and no direct interaction data
   • Apparent pro-inflammatory directionality conflicts with loss-of-function phenotypes elsewhere and is not reconciled
9. 2023 Medium

   Positioned LACC1 transcriptionally downstream of PPARα and upstream of NF-κB in macrophage pyroptosis, indicating nuclear-receptor control of LACC1 expression as an inflammatory rheostat.

   Evidence Transcriptome sequencing, siRNA knockdown, adenoviral overexpression and western blotting in an EAM mouse model and macrophage lines

   PMID:37976692

   Open questions at the time

   • Pathway placement is pharmacological rather than direct
   • Whether PPARα regulates LACC1 promoter directly not shown
10. 2025 Medium

    Generalized the NOD2-LACC1-ER-stress axis beyond macrophages to microglia, showing LACC1 mediates NOD2-driven neuroinflammation via the ER in sepsis.

    Evidence NOD2 CRISPR knockout mice, siRNA epistasis of NOD2 and LACC1, ER-stress inhibition, CLP sepsis model with ER ultrastructure imaging

    PMID:40335000

    Open questions at the time

    • Direct biochemical link between LACC1 and ER-stress induction in microglia not established
    • Single lab; relationship to LACC1 enzymatic activities not tested

• How LACC1's distinct enzymatic activities (purine phosphorolysis, citrulline conversion) are mechanistically unified within one protein and how they map onto its peroxisomal, mitochondrial and ER localizations to produce each immune phenotype remains unresolved.
• No structural model integrating the multiple catalytic activities
• Mechanism of stimulus-dependent relocalization across organelles unknown
• Causal chain from a single catalytic activity to each in vivo immune phenotype not isolated