Carnosine Synthase (TsATPGD) Alleviates Lipid Peroxidation Under Transcriptional Control by an Nfe2-like Gene in Tridacna Squamosa

As an important mollusk in reef ecosystems, <i>Tridacna squamosa</i> forms pro-survival symbiotic relationships that hinge on an exquisite redox equilibrium between the host and the photosynthetic symbiont, zooxanthellae. The exact regulatory mechanisms thereof remain poorly understood. In this study, a novel Nfe2-like transcription factor in <i>T. squamosa</i> was identified and characterized with respect to its antioxidant and cytoprotective roles. Gene structure and phylogenetic analysis reveal that <i>T. squamosa</i> possesses a single transcription factor <i>Ts</i>Nfe2l in contrast to mammalian Nfe2l1 (Nrf1) and Nfe2l2 (Nrf2), belonging to protein members of the bZIP-NFE2 subfamily and functionally resembling the mammalian Nfe2l1. A conserved bZIP domain permits its binding to the antioxidant response element (ARE) in vitro and in HEK293T cells. Further analyses such as promoter prediction suggest that <i>Ts</i>Nfe2l target genes engage mainly in the regulation of multiple enzymes involved in antioxidation and allied pathways. Notably, <i>Ts</i>Nfe2l transcriptionally upregulates carnosine synthase (<i>Ts</i>ATPGD), which subsequently produces <i>L</i>-carnosine abundantly to shield cells from oxidative damage. Moreover, the blockage of <i>Ts</i>Nfe2l nucleic acid binding reduced the expression of <i>Ts</i>ATPGD and <i>L</i>-carnosine content in the gill, resulting in elevated lipid peroxidation. Collectively, our findings establish novel molecular insight into <i>Ts</i>Nfe2l as a critical regulator of redox homeostasis in <i>T. squamosa</i> through carnosine synthesis.