Sensing and regulation of long-chain polyunsaturated fatty acids pool in marine mollusks: Characterization of UBXD8 from the razor clam Sinonovacula constricta

The razor clam Sinonovacula constricta is known for its richness in long-chain polyunsaturated fatty acids (LCPUFA, C >= 20). Previously, we demonstrated that it possesses a complete LC-PUFA biosynthetic pathway. However, the mechanisms by which it senses the LC-PUFA pool to regulate their biosynthesis remain unclear. Here, we presented the LC-PUFA sensor UBXD8 as a critical molecule in this intriguing process. The S. constricta UBXD8 (ScUBXD8) shared all characteristic features of its mammalian counterpart and exhibited high mRNA levels in digestive tissues, suggesting its functional role in this bivalve species. By purification of ScUBXD8 protein in vitro, we discovered its ability to sense unsaturated fatty acids (UFA, C >= 14) but not saturated ones, as evidenced by polymerization detection. Furthermore, the intensity of ScUBXD8 polymerization increased progressively with longer acyl chain lengths, greater unsaturation degrees, and higher UFA concentrations. Exceptionally, for those located at the same node in LC-PUFA biosynthetic pathway, ScUBXD8 displayed a stronger sensitivity to n-6 UFA compared to n-3 UFA. These results suggested a critical role for ScUBXD8 in balancing fatty acids composition and ratio of n-6/n-3 UFA in S. constricta. Moreover, the UAS domain was confirmed essential for ScUBXD8 polymerization. Through knockdown of ScUbxd8 gene in vivo, there were significant shifts in expression patterns of genes related to LC-PUFA biosynthesis, concurrently influencing fatty acids compositions. These results suggested that ScUBXD8 likely plays a regulatory role in LC-PUFA biosynthesis, possibly through the INSIG-SREBP pathway. Collectively, this study proposed that S. constricta might maintain LC-PUFA homeostasis through UBXD8 to regulate their biosynthesis.