A large number of RNAs are not diffusely distributed in the cytoplasm, but are actively transported to various subcellular sites. After reaching their final destinations, localized RNAs are translated, thus directing local protein production. While increasing numbers of localized RNAs are being identified, the functional importance of these events is not well understood. We are focusing on a localization pathway that we have identified, which targets a number of RNAs to the tips of cellular protrusions. We have found that an important component of this pathway is the tumor-suppressor protein Adenomatous Polyposis Coli (APC) whose mutation is the initiating event in the progression of the majority of colorectal cancers. APC associates with RNAs at cellular protrusions in ribonucleoprotein complexes, which we term APC-RNPs. An additional component of APC-RNPs is the RNA-binding protein Fus/TLS, a protein whose mutation has been linked to both cancer and Amyotrophic Lateral Sclerosis (ALS). We have recently shown that ALS-associated mutants of Fus mislocalize APC-RNPs in internal cytoplasmic granules and misdirect their translation. During the last year, we have made significant progress in understanding how APC-RNP localization is regulated, and in identifying cellular factors involved in this process. Specifically, we have found that characteristics of the extracellular matrix environment can affect APC-RNP localization. This effect appears to be mediated through modulation of the cytoskeletal architecture, and we have made inroads in identifying the cytoskeletal components involved. We have additionally found that pathogenic mutations in the Fus protein lead to APC-RNP mislocalization through similarly affecting cytoskeletal architecture and dynamics. Interestingly, this effect is dependent on aggregation of the mutant Fus protein, a transition that is linked to triggering of late-onset diseases associated with Fus mutations (such as ALS and FTLD). Finally, we have devised a strategy to induce APC-RNP mislocalization in cellular systems and are currently characterizing the contribution of APC-RNP localization in various migratory parameters in 2D and 3D migration systems.
| Yasuda, Kyota; Clatterbuck-Soper, Sarah F; Jackrel, Meredith E et al. (2017) FUS inclusions disrupt RNA localization by sequestering kinesin-1 and inhibiting microtubule detyrosination. J Cell Biol 216:1015-1034 |
| Yasuda, Kyota; Mili, Stavroula (2016) Dysregulated axonal RNA translation in amyotrophic lateral sclerosis. Wiley Interdiscip Rev RNA 7:589-603 |
| Yasuda, Kyota; Zhang, Huaye; Loiselle, David et al. (2013) The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules. J Cell Biol 203:737-46 |
