Lin, I.-J. | bioRxiv Science

bioRxiv2024

Unraveling the immunological roles of serum amyloid A3 in aortic immune cell subsets during atherosclerosis progression

Atherosclerosis is a growing concern in developed nations, necessitating the identification of therapeutic targets for advancing personalized medicine. Serum amyloid A3 (Saa3) has been linked to accelerated plaque progression by affecting cholesterol metabolism and modulation of inflammation. We hypothesize that knocking out Saa3 (Saa3-/-) could mitigate plaque development by regulating aortic immune cell compositions during atherosclerosis progression. Using a murine model, we induced atherosclerosis via a gain-of-function mutant PCSK9-encoding adeno-associated viral vector (AAVmPCSK9) in female wild-type (WT) and Saa3-/- mice. Saa3-/- mice developed smaller plaques than WT mice, and single-cell RNA sequencing revealed significant differences in aortic immune cell populations, particularly among aortic macrophages. Aortic macrophages in atherosclerotic Saa3-/-mice represent an anti-inflammatory and tissue-repairing phenotype and the Trem2hi macrophages, characterized by high Gpnmb, Lpl, and Spp1 expressions, predominated over the typical foamy macrophages in Saa3-/- compared to WT mice. Notably, SAA3 regulates cholesterol metabolism and inflammatory responses in foamy macrophages. Our study highlights Saa3 as a key modulator of aortic immune cells that impact atherosclerosis progression.

immunology↗

bioRxiv2022

The evolution and structure of snake venom phosphodiesterase (svPDE) highlight its importance in venom actions

For decades, studies of snake venoms focused on the venom-ome-specific toxins (VSTs). VSTs are dominant soluble proteins believed to contribute to the main venomous effects and emerged into gene clusters for fast adaptation and diversification of snake venoms. However, the conserved minor venom components, such as snake venom phosphodiesterase (svPDE), remain largely unexplored. Here, we focus on svPDE by genomic and transcriptomic analysis across snake clades and demonstrate that soluble svPDE is co-opted from the ancestral membrane-attached ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase 3) gene by replacing the original 5 exon with the exon encoding a signal peptide. Notably, the exons, promoters and transcription/translation starts have been replaced multiple times during snake evolution, suggesting the evolutionary necessity of svPDE. The structural and biochemical analyses also show that svPDE shares the similar functions with ENPP family, suggesting its perturbation to the purinergic signaling and insulin transduction in venomous effects. Significance StatementWe provided a case of the evolutionary co-option strategy in which the secretory svPDE, one of the minor venom components, is generated from the ancestral membrane-anchored ENPP3 gene by using an alternative 5 exon. The first exon of the svPDE transcript encodes a signal peptide instead of the transmembrane domain of the ENPP3. Multiple replacement events of genomic elements during snake evolution maintain the expression of the svPDE transcripts, suggesting the crucial function of svPDE. Also, the structures and biochemical analyses indicate that svPDE reuse the original functions of ENPP3 in the bitten tissues and may interfere with normal cell signaling. Together, our study reveals the evolution of svPDE and suggests the importance of minor venom components.

evolutionary biology↗