Disrupting PQBP1-eEF2 protein-protein interaction: From synaptic translation to immunity and cancer

Polyglutamine-binding protein 1 (PQBP1) has emerged as a multifaceted regulator of gene expression, acting not only in the nucleus to influence transcription and splicing but also in the cytoplasm to control protein synthesis. A recent discovery identified a direct interaction between PQBP1 and the translation elongation factor eEF2, unveiling a new checkpoint in the elongation phase of protein synthesis. PQBP1 binds preferentially to the non-phosphorylated form of eEF2 and protects it from phosphorylation at Thr56 by its kinase eEF2K. Through this mechanism, PQBP1 promotes continuous elongation under conditions where unchecked eEF2K activity would otherwise stall ribosomes. The PQBP1-eEF2 complex plays critical roles in maintaining global proteome homeostasis and enabling activity-dependent protein synthesis in neurons. Disruption of this protein-protein interaction (PPI), whether by genetic mutations in PQBP1 or by sequestration of PQBP1 in cellular aggregates, has been linked to pathological states ranging from intellectual disability and impaired synaptic plasticity to altered innate immune responses and possibly tumorigenesis. In this review, we summarize the current understanding of the PQBP1-eEF2 interaction, its structural basis and regulation, the physiological processes it governs, and the consequences of its disruption in disease. We also discuss therapeutic considerations - when stabilizing this interaction might be beneficial (e.g. to restore synaptic function in neurodegeneration) versus when inhibiting it could be advantageous (e.g. to dampen excessive translation in cancer). Finally, we highlight experimental strategies and open questions for future research on this newly recognized nexus of translation control.