hnRNPs Interacting with mRNA Localization Motifs Define AxoNAl RNA Regulons

Lee, Seung Joon; Oses-Prieto, Juan A.; Kawaguchi, Riki; Sahoo, Pabitra K.; Kar, Amar N.; Rozenbaum, Meir; Oliver, David J.; Chand, Shreya; Ji, Hao; Shtutman, Michael; Miller-Randolph, Sharmina; Taylor, Ross; Fainzilber, Mike; Coppola, Giovanni; Burlingame, Alma L.; Twiss, Jeffery L.

doi:10.1074/mcp.ra118.000603

Cited by 30 publications

(21 citation statements)

References 66 publications

(85 reference statements)

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“…Although multiplexing analyses would be required to obtain an extensive cartography of the exact repertoire of granules present at a given time point in neuronal compartments, these experiments have rather revealed that multiple types of granules, containing varying overlapping subsets of proteins, are present along neuronal extensions. Further consistent with this idea, only a partial overlap was observed in the protein content of RNP complexes exogenously assembled on distinct axonally‐localized RNAs, or in the protein content of two distinct types of dendritic RNP granules purified biochemically based on the selective presence of the Staufen 2 and Barentsz RBPs . Together, these results suggested that a restricted number of proteins (eg, Pur‐α, or DDX‐6 and Yb1 in dendrites) may be present in various types of granules, potentially representing a core set of constitutive factors required for granule assembly/maintenance, while a larger number of RBPs (eg, Staufen 2, Barentsz, FMRP, ZBP1, HuR or cytoplasmic polyadenylation element binding (CPEB)) may be recruited to specific granule species for defined regulatory functions .…”

Section: A Heterogenous Collection Of Granulessupporting

confidence: 53%

Neuronal ribonucleoprotein granules: Dynamic sensors of localized signals

Formicola

Vijayakumar

Besse

2019

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Membrane-less organelles, because of their capacity to dynamically, selectively and reversibly concentrate molecules, are very well adapted for local information processing and rapid response to environmental fluctuations. These features are particularly important in the context of neuronal cells, where synapse-specific activation, or localized extracellular cues, induce signaling events restricted to specialized axonal or dendritic subcompartments. Neuronal ribonucleoprotein (RNP) particles, or granules, are nonmembrane bound macromolecular condensates that concentrate specific sets of mRNAs and regulatory proteins, promoting their long-distance transport to axons or dendrites. Neuronal RNP granules also have a dual function in regulating the translation of associated mRNAs: while preventing mRNA translation at rest, they fuel local protein synthesis upon activation. As revealed by recent work, rapid and reversible switches between these two functional modes are triggered by modifications of the networks of interactions underlying RNP granule assembly. Such flexible properties also come with a cost, as neuronal RNP granules are prone to transition into pathological aggregates in response to mutations, aging, or cellular stresses, further emphasizing the need to better understand the mechanistic principles governing their dynamic assembly and regulation in living systems. K E Y W O R D S biological condensates, local translation, neuronal compartments, neuronal RNA granule, RNP complex 1 | INTRODUCTION Neurons are highly polarized cells specialized in complex information processing, transfer and local storage. They are compartmentalized into macroscopic functional domains-the dendrites, soma and axons-themselves further divided into operational subcompartments locally integrating external signals. 1 These subcompartments are not defined by structural boundaries, but rather by their enrichment in specialized supramolecular complexes. Axon growth cones, for example, are enriched in signaling molecules, components of the protein synthesis and degradation machineries, and cytoskeletal regulators, that together promote physical turning or collapse in response to chemical or mechanical guidance cues. 2,3 Dendritic spines are enriched in postsynaptic proteins such as transmembrane receptors, channels and downstream signal transduction components modulating synaptic strength in response to neuronal activation or inhibition. 4-7Remarkably, neuronal subcompartments are highly plastic and undergo extensive remodeling of their proteomes in response to external cues. 8,9 Such a remodeling involves local protein synthesis of new proteins, a process achieved via the translation activation of localized mRNAs transported from the soma in a translationally silent Nadia Formicola and Jeshlee Vijayakuma contributed equally to this study.

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Section: A Heterogenous Collection Of Granulessupporting

confidence: 53%

Neuronal ribonucleoprotein granules: Dynamic sensors of localized signals

Formicola

Vijayakumar

Besse

2019

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“…For instance, hnRNP A2/B1 was found to interact with Netrin-1 DCC, which binds a subset of mRNAs involved in cell-cell adhesion and protein targeting, inducing the translation of specific subsets of mRNAs [69,70]. HnRNP H1, H2, and F are also involved in regulating axonal mRNA regulation [71]. It was found that a combined knockdown reduced levels of axonal Hmgb1 and Nrn1 mRNA levels, and decreased axonal protein synthesis [71].…”

Section: Axonal Transportmentioning

confidence: 99%

“…HnRNP H1, H2, and F are also involved in regulating axonal mRNA regulation [ 71 ]. It was found that a combined knockdown reduced levels of axonal Hmgb1 and Nrn1 mRNA levels, and decreased axonal protein synthesis [ 71 ]. With the diverse roles of hnRNPs in maintaining neuronal health and the dire consequences when perturbed, it is reasonable to postulate that neurodegeneration can be precipitated by the misregulation of hnRNP in the neuronal parenchyma.…”

Section: Function Of Hnrnpsmentioning

confidence: 99%

Heterogeneous Nuclear Ribonucleoproteins: Implications in Neurological Diseases

et al. 2020

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Heterogenous nuclear ribonucleoproteins (hnRNPs) are a complex and functionally diverse family of RNA binding proteins with multifarious roles. They are involved, directly or indirectly, in alternative splicing, transcriptional and translational regulation, stress granule formation, cell cycle regulation, and axonal transport. It is unsurprising, given their heavy involvement in maintaining functional integrity of the cell, that their dysfunction has neurological implications. However, compared to their more established roles in cancer, the evidence of hnRNP implication in neurological diseases is still in its infancy. This review aims to consolidate the evidences for hnRNP involvement in neurological diseases, with a focus on spinal muscular atrophy (SMA), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), multiple sclerosis (MS), congenital myasthenic syndrome (CMS), and fragile X-associated tremor/ataxia syndrome (FXTAS). Understanding more about hnRNP involvement in neurological diseases can further elucidate the pathomechanisms involved in these diseases and perhaps guide future therapeutic advances.

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“…Caspase-3 proteolysis of RBPs, like other mechanisms that regulate RBPs (Hornberg and Holt, 2013;Cioni et al, 2018;Leidal and Debnath, 2020;O'Brien et al, 2020), may therefore serve two parallel functions in auditory brainstem development: Cleavage of RBPs that protect and compartmentalize RNA in growth cones, and cleavage of RBPs that load and transport RNA in EVs. RBPs such as the HNRNP family, six of which are ABC3 substrates, are known to be involved in both processes, so the two functions are not mutually exclusive (Liu et al, 2008;Glinka et al, 2010;Hentze et al, 2018;Lee et al, 2018;Statello et al, 2018;Thelen and Kye, 2020). Caspase-3 may thus influence translation in the growth cone and in neighboring cells simultaneously by cleaving a single RBP.…”

Section: Functional Transfer Of Rna In Evsmentioning

confidence: 99%