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Huffstutler, R. D.

Publications and source records attributed to Huffstutler, R. D..

2 recordsLinked to original sources
bioRxiv2026

ISG15 orchestrates dynamic crosstalk between mitochondrial fat oxidation and type 1 interferon in myeloid cells

In contrast to Krebs cycle intermediates, the role of mitochondrial fatty acid oxidation (FAO) in immunometabolism remains incompletely characterized. Studying primary bone marrow-derived macrophages (BMDMs), we show that IFN-{beta} and STING activation augments FAO and associated enzymes carnitine palmitoyltransferase 1a (CPT1a) and acetyl-CoA acetyltransferase 1 (ACAT1). Depleting BMDM Cpt1a reduces FAO and dampens type 1 interferon (IFN) signaling due to decreased histone H3-K9/K14 acetylation, supporting the prior finding of an epigenetic role of FAO in sustaining type 1 IFN. Interestingly, FAO induction by IFN was dynamic as a heightened IFN response suppressed FAO, suggesting a concurrent negative-feedback mechanism. This FAO blunting correlated with increased expression of interferon-stimulated gene 15 (ISG15), a ubiquitin-like modifier known to modulate metabolic proteins through ISGylation. This immune-metabolic signature was similarly operational in mice infected with lymphocytic choriomenigitis virus (LCMV) with temporal discordance between ISG15 levels and FAO. The role of ISG15 in this negative feedback was shown with increased FAO and type 1 IFN response in Isg15 knockout BMDMs. Parallely, endogenous co-immunoprecipitation showed interactions between ISG15 and CPT1a/ACAT1. This ISG15-FAO regulatory interaction was also evident in systemic lupus erythematosus (SLE)-associated interferonopathy and in primary monocytes from SLE individuals that exhibited increased ISG15 levels and reduced FAO rates. Collectively, these findings support a model in which type 1 IFN initially enhances FAO to amplify interferon production, but excessive IFN-signaling induces ISG15-mediated inhibition of FAO, a putative feedback loop that restrains inflammation and preserves immune homeostasis. Together these data identify a novel biphasic FAO-dependent immunometabolic regulatory program. Graphical Summary O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/700051v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@13f572eorg.highwire.dtl.DTLVardef@174b6aeorg.highwire.dtl.DTLVardef@1856483org.highwire.dtl.DTLVardef@89e5a6_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIType 1 IFN rewires myeloid cell metabolism towards FAO. C_LIO_LIFAO epigenetically fuels Type 1 1IFN response. C_LIO_LIEffect of IFN on FAO is dynamic: inducing FAO at low concentrations while suppressing it during a heightened IFN response. C_LIO_LIEnhanced Type 1 IFN response produces ISG15 which ISGylates key enzymes of FAO altering their stability C_LIO_LIISG15 negatively regulates FAO to control Type 1 IFN homeostasis in a negative feedback loop. C_LI

immunology↗
bioRxiv2024

The mitochondrial thiolase ACAT1 regulates monocyte/macrophage type I interferon via epigenetic control.

Lipid-derived acetyl-CoA is shown to be the major carbon source for histone acetylation. However, there is no direct evidence demonstrating lipid metabolic pathway contribututions to this process. Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) catalyzes the final step of {beta}-oxidation, the aerobic process catabolizing fatty acids (FA) into acetyl-CoA. To investigate this in the context of immunometabolism, we generated macrophage cell line lacking ACAT1. 13C-carbon tracing combined with mass spectrometry confirmed incorporation of FA-derived carbons into histone H3 and this incorporation was reduced in ACAT1 KO macrophage cells. RNA-seq identified a subset of genes downregulated in ACAT1 KO cells including STAT1/2 and interferon stimulated genes (ISGs). CHIP analysis demonstrated reduced acetyl-H3 binding to STAT1 promoter/enhancer regions. Increasing histone acetylation rescued STAT1/2 expression in ACAT1 KO cells. Concomitantly, ligand triggered IFN{beta} release was blunted in ACAT1 KO cells and rescued by reconstitution of ACAT1. Furthermore, ACAT1 promotes FA-mediated histone acetylation in an acetylcarnitine shuttle-dependent manner. In patients with obesity, levels of ACAT1 and histone acetylation are abnormally elevated. Thus, our study identified a novel link between ACAT1 mediated FA metabolism and epigenetic modification on STAT1/2 that uncovers a regulatory role of lipid metabolism in innate immune signaling and opens novel avenues for interventions in human diseases such as obesity.

immunology↗