RanBP2/Nup358 enhances miRNA activity by sumoylating Argonautes

Mutations in RanBP2 (also known as Nup358), one of the main components of the cytoplasmic filaments of the nuclear pore complex, contribute to the overproduction of acute necrotizing encephalopathy (ANE1)-associated cytokines. Here we report that RanBP2 represses the translation of the interleukin 6 (IL6) mRNA, which encodes a cytokine that is aberrantly up-regulated in ANE1. Our data indicates that soon after its production, the IL6 messenger ribonucleoprotein (mRNP) recruits Argonautes bound to let-7 microRNA. After this mRNP is exported to the cytosol, RanBP2 sumoylates mRNP-associated Argonautes, thereby stabilizing them and enforcing mRNA silencing. Collectively, these results support a model whereby RanBP2 promotes an mRNP remodelling event that is critical for the miRNA-mediated suppression of clinically relevant mRNAs, such as IL6.
Author summary RanBP2 (also known as Nup358) is one of the main components of the cytoplasmic filaments of the nuclear pore complex. It has been speculated that RanBP2, which has a SUMO E3-ligase domain, may alter the composition of messenger ribonucleoprotein (mRNP) complexes as they emerge from the nuclear pore and thus regulate the ultimate fate of the mRNAs in the cytoplasm. Five separate missense mutations in RanBP2 cause acute necrotizing encephalopathy 1 (ANE1), which manifests as a sharp rise in cytokine production after common viral infections such as influenza and parainfluenza. However, how RanBP2 and its ANE1-associated mutations affect cytokine production is not well understood. Here we find that Argonaute proteins can be loaded onto mRNAs in the nucleus and upon their nuclear export become sumoylated by RanBP2. This in turn leads to the stabilization of Argonaute-mRNA complexes in the cytosol and enforces silencing of clinically relevant mRNAs, such as interleukin-6 (IL6). These finding presents one of the few biochemical characterizations of an mRNP remodeling event that occurs on the nuclear pore, and opens the possibility that cells control ANE1-associated cytokines via the interplay between RanBP2, microRNA-mediated silencing pathways, and post-translational regulation of proteins.