p38α Mitogen-Activated Protein Kinase Depletion and Repression of Signal Transduction to Translation Machinery by miR-124 and -128 in Neurons

The p38 alpha to p38 delta mitogen-activated protein kinases (MAPKs) are central regulatory nodes coordinating acute stress and inflammatory responses. Their activation leads to rapid adjustment of protein synthesis, for instance translational induction of proinflammatory cytokines. The only known direct link of p38 to translation machinery is the MAPK signal-integrating kinase Mnk. Only p38 alpha and p38 beta transcripts are ubiquitously expressed. These mRNAs encode highly conserved proteins that equally phosphorylate recombinant Mnk1 in vitro. We discovered that expression of the p38 alpha protein, but not the p38 beta isoform, is suppressed in the brain. This is due to p38 alpha depletion by two neuron-selective microRNAs (miRNAs), miR-124 and -128. Suppression of p38 alpha protein was reversed by miR-124/-128 antisense oligonucleotides in primary explant neuronal cultures. Targeted p38 alpha depletion reduced Mnk1 activation, which cannot be compensated by p38 beta. Our research shows that p38 alpha alone controls acute stress and cytokine signaling from p38 MAPK to translation machinery. This regulatory axis is greatly diminished in neurons, which may insulate brain physiology and function from p38 alpha-Mnk1-mediated signaling.