mRNA Location and Translation Rate Determine Protein Targeting to Dual Destinations

Abstract

Numerous proteins are targeted to two or multiple subcellular destinations where they exert distinct functional consequences. The balance between such differential targeting is thought to be determined post-translationally, relying on protein sorting mechanisms. Here, we show that protein targeting can additionally be determined by mRNA location and translation rate, through modulating protein binding to specific interacting partners. Peripheral localization of the NET1 mRNA and fast translation lead to higher cytosolic retention of the NET1 protein, through promoting its binding to the membrane-associated scaffold protein CASK. By contrast, perinuclear mRNA location and/or slower translation rate favor nuclear targeting, through promoting binding to importins. This mRNA location-dependent mechanism is modulated by physiological stimuli and profoundly impacts NET1 function in cell motility. These results reveal that the location of protein synthesis and the rate of translation elongation act in coordination as a "partner-selection" mechanism that robustly influences protein distribution and function.

Subcytoplasmic location of translation controls protein output

“… 14 – 17 These compartments may enable the generation of unique biochemical translation environments, which have been suggested to be crucial for protein interaction partner selection during protein synthesis. 16 , 18 – 20 However, it is currently largely unknown whether the location of protein synthesis also matters for protein output.…”