Stress-dependent miR-980 regulation of Rbfox1/A2bp1 promotes ribonucleoprotein granule formation and cell survival

Mariya M Kucherenko,Halyna R Shcherbata

doi:10.1038/s41467-017-02757-w

Mariya M Kucherenko, Halyna R Shcherbata

Open Access

https://doi.org/10.1038/s41467-017-02757-w

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Abstract

Upon stress, profound post-transcriptional adjustments of gene expression occur in spatially restricted, subcellular, membraneless compartments, or ribonucleoprotein (RNP) granules, which are formed by liquid phase separation of RNA-binding proteins with low complexity sequence domains (LCDs). Here, we show that Rbfox1 is an LCD-containing protein that aggregates into liquid droplets and amyloid-like fibers and promiscuously joins different nuclear and cytoplasmic RNP granules. Using Drosophila oogenesis as an in vivo system for stress response, we demonstrate a mechanism by which Rbfox1 promotes cell survival. The stress-dependent miRNA miR-980 acts to buffer Rbfox1 levels, since it targets only those Rbfox1 transcripts that contain extended 3′UTRs. Reduced miR-980 expression during stress leads to increased Rbfox1 levels, widespread formation of various RNP granules, and increased cell viability. We show that human RBFOX proteins also contain multiple LCDs and form membraneless compartments, suggesting that the RNP granule-linked control of cellular adaptive responses may contribute to a wide range of RBFOX-associated pathologies in humans.

Highlights

Upon stress, profound post-transcriptional adjustments of gene expression occur in spatially restricted, subcellular, membraneless compartments, or ribonucleoprotein (RNP) granules, which are formed by liquid phase separation of RNA-binding proteins with low complexity sequence domains (LCDs)
There is increasing evidence for spatial and temporal regulation of gene expression at the post-transcriptional level[1]. This often involves the formation of specialized membraneless compartments, or ribonucleoprotein (RNP) granules, called liquid organelles, which are formed by proteins containing RNAbinding and low complexity sequence domains (LCDs)[2,3,4]
Drosophila miR-980 was previously identified as stresslinked in a screen for miRNAs that are differentially expressed in response to stress and disease17. miR-980 was found to be downregulated upon various stresses (Supplementary Table 1), suggesting that it could play a role in stress tolerance

Summary

Introduction

Profound post-transcriptional adjustments of gene expression occur in spatially restricted, subcellular, membraneless compartments, or ribonucleoprotein (RNP) granules, which are formed by liquid phase separation of RNA-binding proteins with low complexity sequence domains (LCDs). There is increasing evidence for spatial and temporal regulation of gene expression at the post-transcriptional level[1] This often involves the formation of specialized membraneless compartments, or ribonucleoprotein (RNP) granules, called liquid organelles, which are formed by proteins containing RNAbinding and low complexity sequence domains (LCDs)[2,3,4]. Relative Rbfox[1] band intensity WT Sated WT Starved miR-980 Ex1–2 Sated miR-980 Ex1–2 Starved a Control Sated All of these structures are highly dynamic and often form or increase in size and number upon specific changes in the cellular or organismal environment

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