RNA binding proteins PCBP1 and PCBP2 regulate pancreatic β cell translation

Tight control of β cell mRNA translation plays a central role in regulating glucose homoeostasis and β cell health. RNA binding proteins (RBPs) impact translational dynamics and function in networks to achieve their regulatory outcomes, yet an understanding of the RBPs and nature of their interplay in directing β cell translation remain limited. We recently established that the RBP PCBP2 is a key post-transcriptional regulator of β cell function. Here, we investigate the relationship of PCBP2 and its sister-isoform PCBP1 in shaping β cell homeostasis and translation. Pcbp co-deletion in primary β cells gave rise to a severe diabetic phenotype due to compromised β cell viability. Single-cell RNA sequencing of Pcbp co-deficient β cells revealed downregulation of a network of core translation initiation factors and ribosomal mRNAs. Motif enrichment analysis, mRNA-protein interaction, and mRNA stability studies identified that the PCBPs co-impact these mRNAs in part through binding and stabilization. Accordingly, protein translational monitoring demonstrated a requirement for the PCBPs in sustaining global mRNA translation in β cells. Together, these findings demonstrate a requirement for the PCBPs in sustaining the global rates of mRNA translation critical for β cell control of glucose homeostasis. Islets were isolated from 4-5 week old, male Pcbp1/2Fl/Fl or Pcbp1/2βKO mice, hand-picked clean of acinar, and recovered for 3 days in RPMI 1640 medium.