FUS inclusions disrupt RNA localization by sequestering kinesin-1 and inhibiting microtubule detyrosination

Yasuda, Kyota; Soper, Sarah F. Clatterbuck; Jackrel, Meredith E.; Shorter, James; Mili, Stavroula

doi:10.1083/jcb.201608022

Cited by 98 publications

(107 citation statements)

References 73 publications

(110 reference statements)

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“…How MT modifications impact transport of RNA cargoes is largely unexplored. To our knowledge, APC-dependent RNAs are the first group of RNAs that require a specific set of modified microtubules, namely detyrosinated microtubules, for their localization, as shown in this work and supported by additional recent work from our group 54 .…”

Section: Discussionsupporting

confidence: 73%

Extracellular matrix stiffness and cell contractility control RNA localization to promote cell migration

et al. 2017

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Numerous RNAs are enriched within cellular protrusions, but the underlying mechanisms are largely unknown. We had shown that the APC (adenomatous polyposis coli) protein controls localization of some RNAs at protrusions. Here, using protrusion-isolation schemes and RNA-Seq, we find that RNAs localized in protrusions of migrating fibroblasts can be distinguished in two groups, which are differentially enriched in distinct types of protrusions, and are additionally differentially dependent on APC. APC-dependent RNAs become enriched in high-contractility protrusions and, accordingly, their localization is promoted by increasing stiffness of the extracellular matrix. Dissecting the underlying mechanism, we show that actomyosin contractility activates a RhoA-mDia1 signaling pathway that leads to formation of a detyrosinated-microtubule network, which in turn is required for localization of APC-dependent RNAs. Importantly, a competition-based approach to specifically mislocalize APC-dependent RNAs suggests that localization of the APC-dependent RNA subgroup is functionally important for cell migration.

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Section: Discussionsupporting

confidence: 73%

Extracellular matrix stiffness and cell contractility control RNA localization to promote cell migration

et al. 2017

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“…Lastly, given that protein aggregation and phase separation are tightly controlled by the cell’s protein degradation and chaperone machinery [101,104,105,136], ongoing efforts are focused on finding drugs that upregulate these pathways [137], or on the generation of potent engineered disaggregases which could antagonize pathological phase transitions [138,139]. Unraveling the complex regulation of protein phase separation will be key in identifying new pathways, which could be targeted to correct pathological phase transitions.…”

Section: Road Toward Novel Therapy?mentioning

confidence: 99%

Protein Phase Separation: A New Phase in Cell Biology

Boeynaems

Alberti

Fawzi

et al. 2018

Trends in Cell Biology

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Cellular compartments and organelles organize biological matter. Most well-known organelles are separated by a membrane boundary from their surrounding milieu. There are also many so-called membraneless organelles and recent studies suggest that these organelles, which are supramolecular assemblies of proteins and RNA molecules, form via protein phase separation. Recent discoveries have shed light on the molecular properties, formation, regulation, and function of membraneless organelles. A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders.

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“…Fused in sarcoma (FUS), a DNA and RNA-binding protein that shuttles between the nucleus and cytoplasm, and functions in DNA repair, transcription, splicing and mRNA transport (Qui et al 2014; Reber et al 2016; Yasuda et al 2017), is yet another link between the neurodegenerative diseases SMA and ALS. Mutations in FUS are associated with cases of familial ALS and aberrant FUS-positive aggregates have been detected in motor and spinal neurons (Kwiatkowski et al 2009; Vance et al 2009).…”

Section: Hypoxic Stressmentioning

confidence: 99%

SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities

2017

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Low levels of the survival of motor neuron (SMN) protein cause the neurodegenerative disease spinal muscular atrophy (SMA). SMA is a pediatric disease characterized by spinal motor neuron degeneration. SMA exhibits several levels of severity ranging from early antenatal fatality, to only mild muscular weakness and disease prognosis is related directly to the amount of functional SMN protein that a patient is able to express. Current therapies are being developed to increase the production of functional SMN protein, however understanding the effect that natural stresses have on the production and function of SMN is of critical importance to ensuring that these therapies will have the greatest possible effect for patients. Research has shown that SMN, both on the mRNA and protein level, is highly affected by cellular stress. In this review we will summarize the research that highlights the roles of SMN in the disease process and the response of SMN to various environmental stresses.

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FUS inclusions disrupt RNA localization by sequestering kinesin-1 and inhibiting microtubule detyrosination

Cited by 98 publications

References 73 publications

Extracellular matrix stiffness and cell contractility control RNA localization to promote cell migration

Extracellular matrix stiffness and cell contractility control RNA localization to promote cell migration

Protein Phase Separation: A New Phase in Cell Biology

SMN regulation in SMA and in response to stress: new paradigms and therapeutic possibilities

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