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Cells have evolved an elaborate network of folding and degradation pathways to maintain the native state of proteins. If these pathways are disrupted (e.g., mutation) or their capacity is exceeded then protein aggregates form in cells. Cells sequester these aggregated proteins into aggresome or aggresome-like bodies as a protective mechanism. In this study, we co-expressed two model misfolded proteins in HEK293 cells and measured aggresome formation upon proteasomal inhibition. We observed spatial differences in early time points of aggresome formation upon co-expression of the misfolded proteins compared to individual expression in cells., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2024 by the authors.)

The Drosophila RNA-binding protein (RBP) Nab2 acts in neurons to regulate neurodevelopment and is orthologous to the human intellectual disability-linked RBP, ZC3H14. Nab2 governs axon projection in mushroom body neurons and limits dendritic arborization of class IV sensory neurons in part by regulating splicing events in ∼150 mRNAs. Analysis of the Sex-lethal ( Sxl ) mRNA revealed that Nab2 promotes an exon-skipping event and regulates m 6 A methylation on Sxl pre-mRNA by the Mettl3 methyltransferase. Mettl3 heterozygosity broadly rescues Nab2 null phenotypes implying that Nab2 acts through similar mechanisms on other RNAs, including unidentified targets involved in neurodevelopment. Here, we show that Nab2 and Mettl3 regulate the removal of a 5'UTR (untranslated region) intron in the trio pre-mRNA. Trio utilizes two GEF domains to balance Rac and RhoGTPase activity. Intriguingly, an isoform of Trio containing only the RhoGEF domain, GEF2, is depleted in Nab2 null nervous tissue. Expression of Trio-GEF2 rescues projection defects in Nab2 null axons and dendrites, while the GEF1 Rac1-regulatory domain exacerbates these defects, suggesting Nab2-mediated regulation Trio-GEF activities. Collectively, these data indicate that Nab2-regulated processing of trio is critical for balancing Trio-GEF1 and -GEF2 activity and show that Nab2, Mettl3, and Trio function in a common pathway that shapes axon and dendrite morphology., Competing Interests: Conflict of interest: The authors declare no financial conflict of interest.