Grant: Operating Grant

Gene expression begins in the nucleus where DNA is transcribed into RNA, which is then processed into mature messenger RNA (mRNA). mRNAs are then packaged into large messenger ribonucleoprotein (mRNP) complexes, which are exported from the nucleus to the cytoplasm, where they are transported to their proper destination. For example, mRNAs that encode secretory and membrane-bound proteins are translated on the surface of the endoplasmic reticulum, a large organelle that is dedicated to secretion. Once localized, these mRNAs are translated into proteins. We have demonstrated that a large majority of mRNA encoding secretory proteins share an element, called the ALREX-element, which promotes the nuclear export and efficient translation of these mRNAs, likely by influencing how the mRNP is built and matured. In the nucleus these mRNAs are assembled into mRNPs within nuclear speckles. Then, after these mRNPs are exported, they interact with RanBP2 through their ALREX-elements. RanBP2 is a large protein that is localized to the cytoplasmic face of the nuclear pore. RanBP2 is known to attach the small peptide SUMO to protein substrates. We believe that RanBP2 sumoylates mRNP components in order to prepare the mRNA for translation. Mutations in RanBP2 are associated with acute necrotizing encephalopathy (ANE1) a condition caused by the hyper-secretion of cytokines. To further advance our understanding of how these mRNAs are regulated we will: 1) Dissect how RanBP2 recognizes ALREX-elements 2) Determine whether sumoylation regulates the translation of these mRNA 3) Determine how RanBP2 alters mRNPs 4) Determine how mRNPs are assembled onto mRNAs that contain ALREX-elements By dissecting how ALREX-elements function, we will gain insight into physiological pathologies where secretion in misregulated, including type 2 diabetes, and ANE1. This work will provide knowledge that will lead to novel therapeutic treatments for these debilitating illnesses.