Uy, J. N. | bioRxiv Science

bioRxiv2026

SCD-dependent lipid metabolism licenses alternative macrophage activation and macrophage plasticity

Lipid metabolic reprogramming accompanies macrophage activation, yet our understanding of why macrophages profoundly reshape their lipid composition remains unclear. Here, we identify stearoyl-CoA desaturase (SCD) as a lipid-metabolic checkpoint required for the acquisition of the alternatively activated macrophage (AAM) cell state. We show that SCD maintains lipid desaturation balance by ensuring the conversion of newly synthesized saturated long-fatty acids (SFAs) into monounsaturated fatty acids (MUFAs). Critically, disruption of SCD resulted in the rapid accumulation of saturated phosphatidic acid (PA) and hyperactivation of mTORC1, which perturbed the acquisition of stable AAM epigenetic and transcriptional programs. Notably, inhibition of upstream lipogenic enzymes (e.g., ACC and FASN) did not impair AAM polarization, underscoring that an imbalance between newly synthesized saturated and monounsaturated fatty acids, not the loss of de novo lipogenesis, determines AAM identity. Unexpectedly, the loss of SCD redirected IL-4-activated macrophages into an aberrant cell state poised for pro-inflammatory responses, indicating that disruption of this lipid metabolic checkpoint leads to misinterpretation of anti-inflammatory instructional cues. Rescue of SCD-deficient macrophages via mTORC1 inhibition confirmed a causal role for the SCD-PA-mTORC1 axis in controlling macrophage plasticity. Finally, we find that SCD deficiency and resultant PA accumulation attenuated Toxoplasma gondii-driven AAM polarization and reduced pathogen burden. Together, these data establish the SCD-PA lipid signaling axis as a critical metabolic regulator of macrophage plasticity with direct consequences for host defense.

immunology↗

bioRxiv2025

Toxoplasma IMC1 is a central component of the subpellicular network and plays critical roles in parasite morphology, replication, and infectivity

Toxoplasma gondii and related apicomplexan parasites utilize a unique membrane and cytoskeletal organelle called the inner membrane complex (IMC) for maintaining cell shape, motility, host cell invasion, and replication. The cytoskeleton portion of the organelle is a network of filaments composed of proteins called alveolins, whose precise functions and organization are poorly understood. Here we describe the function of the founding member of the Toxoplasma alveolins, IMC1, which we show is expressed and loaded onto forming daughter buds with IMC4, but later than the other key alveolins IMC3, IMC6, and IMC10. Disruption of IMC1 results in severe morphological defects that impact the integrity of the parasites cytoskeleton and disrupt invasion, replication, and egress. Loss of IMC1 in a less virulent type II strain results in a dramatic loss of infectivity and complete failure to form a chronic infection. We then use deletion analyses to dissect functional regions of the protein which reveals a key subregion of the alveolin domain that is sufficient for IMC targeting and also required for function. We then show that IMC1 interacts directly with IMC4 and the loss of IMC1 results in mislocalization of IMC4 specifically in forming daughter buds. This study thus reveals the critical role that IMC1 plays in forming and maintaining the architecture of the filamentous network of the IMC. SignificanceParasites in the phylum Apicomplexa maintain their intracellular lifestyle using specialized organelles that mediate the lytic cycle of host cell invasion, intracellular replication, and egress. One of these organelles is the inner membrane complex (IMC), which consists of membrane vesicles supported by a cytoskeletal meshwork formed from proteins called alveolins. This study focuses on the first identified alveolin IMC1 and determines its precise function via expression timing, gene knockout, deletion and mutagenesis, partner identification, and in vivo infection studies. We show that this protein is critical to the ultrastructure of the parasite which is important for every stage of its lytic cycle. We also identify key regions of the protein that are important for localization, function, and interaction with another key alveolin, IMC4.

microbiology↗