Fig. 9
The miR-980/Rbfox1-mediated stress-responsive signaling cascade. Stress-dependent miR-980 regulates Rbfox1, amending cell survival. miR-980 can target only the portion of Rbfox1 mRNAs with the alternative extended 3′UTRs. This prevents the reduction of Rbfox1 levels below a certain threshold, which is detrimental for cellular homeostasis. Rbfox1 is a LCD-containing protein that phase-separates into liquid droplets and amyloid-like fibers in vivo and promiscuously joins nuclear and cytoplasmic RNP granules. Their assembly depends on Rbfox1 concentration and the presence of alternatively spliced isoforms. Since upon stress or miR-980 loss, the levels of Rbfox1 generally increase, this, via LCD-mediated interactions, stimulates aggregation of other LCD-containing proteins that have specific functions in the nuclear and cytoplasmic liquid organelles. Since Rbfox1 levels globally influence RNA granule dynamics, we propose that the cell survival and differentiation defects observed as a result of Rbfox1 up- or down-regulation could be caused by Rbfox1 function as a liquid droplet-assembling LCD-containing protein
