Biology subjects

Karpac, J.

Publications and source records attributed to Karpac, J..

3 recordsLinked to original sources

bioRxiv2025

NF-κB restrains nutrient-dependent transcription programs through chromatin modulation in Drosophila

The co-evolution of immune and metabolic systems has endowed immune signaling pathways with distinct control of cellular metabolism. Innate immune transcription factors, such as nuclear factor {kappa}B (NF-{kappa}B), have thus emerged as key regulators of adaptive metabolic responses to changes in diet and nutrition. Utilizing chromatin accessibility genomics, we found that Drosophila NF-{kappa}B (Relish) can restrain nutrient-dependent metabolic transcriptional programs that control cellular catabolism of energy substrates, divergent from the proteins canonical role as a transcriptional activator. NF-{kappa}B/Relish restricts chromatin accessibility through modulating histone acetylation at metabolic target gene loci, which restrains metabolic gene transcription and blocks excessive activation of nutrient-dependent metabolic programs. Targeted genetic screening revealed that histone deacetylase 6 (HDAC6) interacts with NF-{kappa}B/Relish at NF-{kappa}B DNA regulatory motifs to limit chromatin accessibility and repress metabolic transcriptional programs. These results highlight that innate immune transcription factors can epigenetically restrain cellular catabolism to fine-tune nutrient-dependent metabolic adaptation.

physiology↗

bioRxiv2025

Diacylglycerol metabolism drives host-pathogen responses during enteric infection in Drosophila

Lipid metabolism is fundamental to cellular homeostasis, supporting energy storage, membrane architecture, and cellular signaling. Beyond these canonical roles, lipids have emerged as critical regulators of host immunity. Here, we define a lipid-driven mechanism that governs host-pathogen interactions by impacting pathogen clearance and thus infection outcomes. Exploiting Drosophila, we show that enteric infection triggers robust accumulation of neutral lipids, and specifically 1,2-diacylglycerols (DAGs), in the midgut. Disruption of DAG biosynthesis or lipid transport in midgut enterocytes (ECs) impairs lipid accumulation and reduces host survival. Conversely, dietary lipid supplementation enhances lipid storage and improves survival. Mechanistically, these lipid-dependent responses regulate defecation, thereby controlling bacterial clearance from the midgut. DAGs can act as signaling lipids that activate protein kinase C (PKC), and DAG accumulation in ECs correlates with elevated PKC activity and calcium signaling in midgut visceral muscle (VM), promoting VM contraction, midgut motility, and expulsion of pathogens via defecation. Together, our findings reveal a previously unrecognized role for DAG metabolism in shaping host defenses.

physiology↗

bioRxiv2021

Mitochondrial dysfunction promotes alternative gasdermin D-mediated inflammatory cell death and susceptibility to infection

Human mutations in mitochondrial-associated genes are associated with inflammatory diseases and susceptibility to infection. However, their mechanistic contributions to immune outcomes remain ill-defined. We discovered that the disease-associated gain-of-function allele Lrrk2G2019S (leucine-rich repeat kinase 2) promotes mitochondrial hyper-fission, depolarization, and oxidative stress in macrophages. In the presence of Lrrk2G2019S-dependent mitochondrial perturbations, AIM2 inflammasome activation promotes more cell death but not more pyroptotic IL-1b release. Instead, inflammasome activation in Lrrk2G2019S macrophages triggers gasdermin D (GSDMD)-mediated mitochondrial pores, driving up ROS-mediated RIPK1/RIPK3/MLKL dependent necroptosis. Consequently, infection of Lrrk2G2019S mice with Mycobacterium tuberculosis elicits hyperinflammation and immunopathology via enhanced neutrophil infiltration. By uncovering that GSDMD promotes non-pyroptotic cell death in Lrrk2G2019S macrophages, our findings demonstrate that altered mitochondrial function can reprogram cell death modalities to elicit distinct immune outcomes. This provides mechanistic insights into why mutations in LRRK2 are associated with susceptibility to chronic inflammatory and infectious diseases. HIGHLIGHTSO_LIAltered mitochondrial homeostasis reprograms cell death modalities C_LIO_LIGSDMD associates with and depolarizes mitochondrial membranes following AIM2 activation C_LIO_LIGSDMD initiates a shift from pyroptotic to necroptotic cell death in Lrrk2G2019S macrophages C_LIO_LILrrk2G2019S elicits hyperinflammation and susceptibility to infection in flies and mice C_LI

immunology↗