A Naturally Synonymous Mutation in SHOC2 Modulates ERK-PFK Cascade to Mediate Thermotolerance Divergence Among Oysters

Abstract Kinase-mediated phosphorylation modifications play a pivotal role in thermal adaptation. Although extensive research has focused on the signaling transduction pathways of specific kinases, such as ERK, in model organisms, their functions and genetic divergence mechanisms in marine species with differential thermal adaptation remain poorly understood. Here, we employed two closely related oyster species inhabiting distinct thermal niches to investigate the genetic regulatory mechanisms underlying differentially heat-activated ERK kinases. Combining ERK inhibition assays with heat stress, followed by proteomic and phosphoproteomic profiling, we systematically analyzed the downstream regulatory network of ERK kinases in oysters, and then firstly reported that the ERK1/2-mediated phosphorylation at conserved PFK Thr775 enhances its enzymatic activity and glycolytic capacity. Genome-wide association analysis further revealed that a synonymous mutation in the Shoc2 gene drives divergent ERK phosphorylation activated patterns between two oyster species by modulating RNA secondary structure stability and expression levels. Our findings demonstrated that the heat-responsive SHOC2-BRAF-ERK-PFK cascade exhibited stronger activation in thermotolerant species, enabling marine ectotherms to fine-tune metabolic responses to environmental temperature variation. This study serves as an experimental case elucidating how genetic variations shape thermal adaptation divergence through phosphorylation-mediated post-translational regulation, thereby providing a molecular framework for adaptive mechanisms of climate variability.