Local Translation in Axons: When Membraneless RNP Granules Meet Membrane-Bound Organelles

Abstract

Eukaryotic cell compartmentalization relies on long-known membrane-delimited organelles, as well as on more recently discovered membraneless macromolecular condensates. How these two types of organelles interact to regulate cellular functions is still largely unclear. In this review, we highlight how membraneless ribonucleoprotein (RNP) organelles, enriched in RNAs and associated regulatory proteins, cooperate with membrane-bound organelles for tight spatio-temporal control of gene expression in the axons of neuronal cells. Specifically, we present recent evidence that motile membrane-bound organelles are used as vehicles by RNP cargoes, promoting the long-range transport of mRNA molecules to distal axons. As demonstrated by recent work, membrane-bound organelles also promote local protein synthesis, by serving as platforms for the local translation of mRNAs recruited to their outer surface. Furthermore, dynamic and specific association between RNP cargoes and membrane-bound organelles is mediated by bi-partite adapter molecules that interact with both types of organelles selectively, in a regulated-manner. Maintaining such a dynamic interplay is critical, as alterations in this process are linked to neurodegenerative diseases. Together, emerging studies thus point to the coordination of membrane-bound and membraneless organelles as an organizing principle underlying local cellular responses.

Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach

“…Among them, the DVL-1, TLE, isoforms 1-4, and TNRC6A proteins, which are common to Wnt and ER signaling, were exclusively found in the NHA9-BioID pool of biotinylated proteins, reinforcing the idea of a specific effect of NUP98-HOXA9 in these two signaling pathways. In line with our findings, previous work showed that in NUP98-HOXA-transduced hematopoietic stem cells, Wnt and ER signaling pathways were dysregulated, which correlated with cellular transformation [67].…”

“…Changes in gene expression by NUP98-HOXA9 might result from its interaction with major transcription factors, such as TFAP2A ( Table S2 ) and the AP-1 transcription factor complex ( Figure 2 and Figure 3 ), and proteins from cytoplasmic RNP granules ( Figure 2 and Figure 3 ), where mRNA is processed for translation or targeted for degradation [ 47 , 65 , 66 , 67 , 68 ]. Chromatin immunoprecipitation (ChIP) experiments showed that NUP98-HOXA9 (but not NUP98 nor HOXA9) binds at genomic regions that are adjacent to the TFAP2A sequence recognition motif, further supporting a potential interaction between the fusion protein and this transcription factor [ 47 ].…”

Anterograde Axonal Transport in Neuronal Homeostasis and Disease

“…The aforementioned β-actin mRNA, for instance, is localized to growth cones by the RBP Zipcode-Binding Protein 1 (ZBP1; Yao et al, 2006 ). mRNA, RBP and ribosomes are co-transported in large RNA granules, which have been linked to stress granules, where mRNA translation is actively repressed (Kanai et al, 2004 ; Sahoo et al, 2018a ; Pushpalatha and Besse, 2019 ). These granules display anterograde and retrograde microtubule-based motor movements (Gumy et al, 2014 ).…”

A Picture Worth a Thousand Molecules—Integrative Technologies for Mapping Subcellular Molecular Organization and Plasticity in Developing Circuits

“…Microdissection and TRAP approaches for isolating RNA have revealed important roles for transcript UTR sequence motifs and transcript trafficking proteins in local translation. mRNAs are transported in phase-separated ribonucleoprotein (RNP) granules over long distances to dendrites and axons to establish local transcriptome pools (Nalavadi et al, 2012;Jung et al, 2014;Das et al, 2019;Liao et al, 2019;Pushpalatha and Besse, 2019;Fukuda et al, 2020;Rhine et al, 2020;Wu et al, 2020; Figure 3). The spatial control of transcript trafficking is based on mRNA sequences found in 3 and 5 untranslated regions (UTRs; Figure 3A) that act as binding sites for trans-acting RBPs (Sahoo et al, 2018;Bae and Miura, 2020).…”