RNA metabolism and disease

Gene expression is a stepwise process involving distinct cellular processes including transcription, pre-mRNA processing, mRNA export, RNA trafficking, and translation. Recent studies have shown that the different steps in this gene regulation pathway are extensively coupled mechanistically by multifunctional factors. Such linkages presumably allow efficient cellular regulation of gene expression to occur simultaneously at numerous stages along the pathway. Building on this concept, recent work from the our lab has demonstrated that the mRNA export factor Gle1 is involved in both the regulation of mRNA export and translation. In mRNA export, Gle1 associates with the nuclear pore complex (NPC) and activates the DEAD-box protein Dbp5 in conjunction with the small molecule inositol hexakisphosphate (IP6). Interestingly, this function is exquisitely sensitive to the ability of Gle1 to self associate at the NPC. Following mRNA export, Gle1 continues to play roles at both translation machinery and in stress granules. Gle1 modulates the DEAD-box protein Ded1 during translation initiation and stimulates Dbp5 during translation termination. Under stress conditions, nonessential mRNAs are routed to stress granules in the cytoplasm for translational repression. The Gle1A isoform is required for this repression, facilitating efficient assembly and disassembly of stress granules. Thus, Gle1 is an important example of proteins that are positioned to control multiple steps of RNA metabolism during gene expression.

Strikingly, mutations in GLE1 have been causally linked to severe forms of human motoneuron diseases, lethal congenital contracture syndrome 1 (LCCS1), as well as amyotrophic lateral sclerosis (ALS).  We recently reported that the molecular functional consequence of the LCCS1 mutation on Gle1 is defective oligomerization of Gle1 at the NPC, while the ALS-linked mutation appears to disturb the carefully balance of distinct functional pools of Gle1. Current studies are focused on further understanding the role of dysfunctional RNA metabolism in other diseases.