Pumilio2 and Staufen2 selectively balance the synaptic proteome.

Neurons have the capacity to adapt to environmental stimuli, a phenomenon termed cellular plasticity. The underlying processes are controlled by a network of RNA-binding proteins (RBPs). Their precise impact, however, is largely unknown. To address this important question, we chose Pumilio2 (Pum2) and Staufen2 (Stau2), which both regulate synaptic transmission. Surprisingly, even though both RBPs dynamically interact with each other in neurons, their respective impact on the transcriptome and proteome is highly selective. Although Pum2 deficiency leads to reduced translation and protein expression, Stau2 depletion preferentially impacts RNA levels and increases protein abundance. Furthermore, we show that Pum2 activates expression of key GABAergic synaptic components, e.g., the GABA A receptor scaffold protein Gephyrin. Consequently, Pum2 depletion selectively reduced the amplitude of miniature inhibitory postsynaptic currents. Together, our data argue for an important role of RBPs to maintain proteostasis in order to control distinct aspects of synaptic transmission. [Display omitted] • Pum2 and Stau2 selectively regulate the neuronal proteome • Stau2 preferentially regulates mRNA levels, while Pum2 activates translation • Pum2 regulates efficient GABAergic transmission Neurons maintain proteome homeostasis (proteostasis) through a network of RNA-binding proteins (RBPs). Schieweck et al. report that the RBPs Pumilio2 (Pum2) and Staufen2 regulate distinct steps in posttranscriptional gene regulations and are both needed for synaptic proteostasis. Thereby, Pum2 activates translation in order to enhance transmission preferentially at inhibitory synapses. [ABSTRACT FROM AUTHOR]