Exosomes drive ferroptosis by stimulating iron accumulation to inhibit bacterial infection in crustaceans
Qian Sun, Jiawen Yang, Ming Zhang, Yongsheng Zhang, Hongyu Ma, Ngoc Tuan Tran, Xiuli Chen, Yueling Zhang, Kok‐Gan Chan, Shengkang Li
Abstract
Ferroptosis, characterized by iron-dependent cell death, has recently emerged as a critical defense mechanism against microbial infections. The present study aims to investigate the involvement of exosomes in the induction of ferroptosis and the inhibition of bacterial infection in crustaceans. Our findings provide compelling evidence for the pivotal role of exosomes in the immune response of crustaceans, wherein they facilitate intracellular iron accumulation and activate the ferroptotic pathways. Using RNA-seq and bioinformatic analysis, we demonstrate that cytochrome P450 (CYP) can effectively trigger ferroptosis. Moreover, by conducting an analysis of exosome cargo proteins, we have identified the participation of six-transmembrane epithelial antigen of prostate 4 (STEAP4) in the regulation of hemocyte ferroptotic sensitivity. Subsequent functional investigations unveil that STEAP4 enhances cellular Fe 2+ levels, thereby triggering Fenton reactions and accelerating CYP-mediated lipid peroxidation, ultimately culminating in ferroptotic cell death. Additionally, the Fe 2+ -dependent CYP catalyzes the conversion of arachidonic acid into 20-hydroxyeicosatetraenoic acid (20-HETE), which activates the peroxisome proliferator-activated receptor (PPAR). Consequently, the downstream target of PPAR, cluster of differentiation 36 (CD36), promotes intracellular fatty acid accumulation, lipid peroxidation, and ferroptosis. These significant findings shed light on the immune defense mechanisms employed by crustaceans and provide potential strategies for combating bacterial infections in this species.