Abstract
SummaryMutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn's disease and leprosy. We developed an unbiased liquid chromatography-mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic orthologs additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5′-thioadenosine phosphorylase activity, hence, combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronizes mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.
Highlights
FAMIN (Fatty Acid Metabolism-Immunity Nexus; LACC1, C13orf31) is strongly linked to human disease (Table S1)
We generated a metabolite library from the human hepatocellular carcinoma cell line HepG2 transfected with FAMIN small interfering RNA, which proliferated less and exhibited reduced glycolysis and Oxidative phosphorylation (OXPHOS) (Figures S1D and S1E)
FAMIN performed a non-redundant role, letting us expect that extracts would contain all cofactors and substrates required for its activity
Summary
FAMIN (Fatty Acid Metabolism-Immunity Nexus; LACC1, C13orf31) is strongly linked to human disease (Table S1). Penetrant mutations, such as C284R, cause juvenile idiopathic arthritis (JIA), Still’s disease (a fever with rash followed by arthritis), or early-onset inflammatory bowel disease (IBD). Mitochondrial and NOX2-dependent reactive oxygen species (ROS) generation, bacterial killing, NOD2- and Toll-like receptor (TLR)-dependent signaling, inflammasome activation, and cytokine secretion are compromised with impaired FAMIN and linked to perturbed mitochondrial function (Cader et al, 2016; Lahiri et al, 2017). Oxidative phosphorylation (OXPHOS) and glycolysis are compromised and total cellular adenosine triphosphate (ATP) reduced in Famin mutant macrophages. How FAMIN, which shares homology with bacterial orthologs (Pfam motif Domain of Unknown Function [DUF] 152), exerts such profound immunometabolic control had remained enigmatic
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