Uncovering the roles of an essential mRNA regulatory factor Gle1 in stress response and disease

Abstract

Eukaryotic cells respond to stress by reprogramming their gene expression program to inhibit global protein synthesis and direct translationally silenced mRNAs to cytoplasmic foci known as stress granules (SGs). SGs function as sites where mRNAs are sorted for storage, decay or translation. SGs are linked with neurodegeneration, cancer and viral infections. However, the molecular mechanisms underlying SG function during stress and in diseases are poorly understood. DEAD-box proteins (Dbps) are RNA-dependent ATPases that mediate changes in mRNA-protein complex (mRNP) structure. Several Dbps, including DDX3, are recruited to SGs and regulate mRNP entry and exit. But, it is unclear how the Dbp activity is regulated in SGs. In the work presented here, we show that human (h) Gle1 is a novel factor of SGs and it regulates SGs by modulating the dynamic equilibrium between SGs and translation through its regulation of DDX3. We further show that two alternatively spliced isoforms of the GLE1 gene perform distinct and non-overlapping functions in a cell; hGle1A is required for SG function, whereas hGle1B functions in SGs. Interestingly, our results also show that an amyotrophic lateral sclerosis (ALS)-linked mutation in GLE1 disrupts functional specificity of hGle1 isoforms and the resulting protein variant is bifunctional. Overall, this study provides insight into the critical roles of hGle1 in SG biology and also gives clues as to how mutation of GLE1 contributes towards ALS pathogenesis.