FUS Helps miRNA Silence Genes. For ALS, What Does It Mean?

March 2, 2018 - als

Silence, please. FUS binds to a protein Argonaute, to miRNAs, and their mRNA targets, compelling gene silencing. [Courtesy of Molecular Cell, Zhang et al., 2018]

The some-more researchers examine and poke a ALS-related protein FUS, a some-more things they find it does. The latest function, reported in a Mar 1 Molecular Cell, is gene silencing mediated by micro RNAs. Using rodent and tellurian mobile assays, researchers led by Jiou Wang, Johns Hopkins University, Baltimore, found that FUS binds to a protein Argonaute, to miRNAs, and their mRNA targets, compelling gene silencing. A FUS mutant that causes a serious form of ALS performs reduction good than wild-type FUS, though either this contributes to pathogenesis is unknown.

“This engaging paper adds a serve turn to a ongoing story,” pronounced Yves Goldberg, INSERM-Université Grenoble Alpes in France. “It is not startling that FUS has a tie with miRNA; what is new is FUS interacting with Argonaute in a cytoplasm and behaving directly on translation.”

More than 50 mutations in FUS have been found in amyotrophic parallel sclerosis (ALS) and frontotemporal insanity (FTD), though how they means illness stays unclear. FUS wears many hats in a nucleus. It functions in DNA repair, transcription, pre-mRNA splicing, choice poly-adenylation, RNA transport, and a prolongation of micro RNAs (miRNAs) (see October 2012 news; September 2013 news). In neurons, it competence also assistance convey and interpret mRNA during synapses (see October 2017 news; for review, see Deng et al., 2014).

A initial idea that FUS competence be busying itself with nonetheless another charge came from a shade for proteins that correlate with Argonaute 2. AGO2 is a protein during a core of a gene silencing formidable miRISC. First authors Tao Zhang and Yen-Ching Wu identified several AGO2 interactors, though FUS held their eyes since of a strong contracting and couple to ALS. The researchers used co-immunoprecipitation to endorse a dual proteins indeed form a span in rodent forebrain lysates and rudimentary fibroblasts. To map where they bind, a authors voiced a array of truncated FUS and AGO2 proteins in tellurian rudimentary kidney cells (HEK293) and checked any construct’s ability to lift down a partner. Binding mapped to a center domain of AGO2 and a RGG2 domain of FUS.

No FUS, No Silence.
Mouse fibroblasts (top) and tellurian HAP1 cells (bottom) expressing wild-type FUS (blue) restrain countenance of a contributor of miRNA activity 3 times some-more than do cells lacking FUS (purple). For a control contributor though silencing sites (right), a participation or deficiency of FUS creates no difference. [Courtesy of Molecular Cell, Zhang et al., 2018]

FUS had been formerly reported to assistance make miRNAs in a iota (Morlando et al., 2012; Dini Modigliani et al., 2014). However, a newly found communication with AGO2 suggests FUS competence also assistance miRNAs reduce their aim mRNAs in a cytoplasm. To exam this, a researchers used cells that demonstrate mRNA encoding a light-generating protein luciferase with a mutated 3′ UTR that can be silenced by a tiny interfering RNA (siRNA). The siRNA mimics miRNA activity though bypasses miRNA production. When a authors knocked out FUS from rodent rudimentary fibroblasts and a tellurian HAP1 dungeon line, a cells illuminated adult 3 times brighter than controls, indicating FUS is indispensable for full-strength gene silencing (image during left). The researchers afterwards monitored luciferase activity in a participation of R495X, a tellurian ALS FUS mutant lacking partial of a RGG2 domain. These cells shined twice as splendid as cells expressing wild-type FUS, indicating reduced Argonaute 2 contracting renders FUS reduction means to boost miRNA activity.

The researchers used microarrays to consult mRNA and miRNA levels in cells expressing R495X. Many miRNAs were somewhat some-more abounding in these cells than in wild-type FUS controls, though levels of their aim mRNAs were as most as sevenfold greater, confirming that reduced FUS-AGO2 contracting disables miRNA activity. Because R495X also misses a FUS chief localization signal, Wang concurred that change in other FUS functions competence minister to a celebrated effects.

How does FUS correlate with miRNA and mRNA? The researchers focused on a specific miRNA, miR-200c, and one of a targets, ZEB-1. In sum, they found that FUS binds not usually to AGO2, though also to miR-200c and ZEB-1, a latter being contingent on miR-200c. FUS and miR-200c assigned adjacent sites on a ZEB-1 3’UTR.

Wang does not know nonetheless how FUS helps reduce mRNA targets, though he has ideas. “FUS competence assistance miRNAs find their twin targets and move them together with AGO2,” he said, observant a plea of doing this in a dungeon bustling with thousands of mRNAs. FUS could also promote AGO2 loading, act as a transitory chaperone, stabilise miRNA binding, or form a membrane-less dungeon by liquid-liquid proviso separation.

Udai Pandey, University of Pittsburgh, finds a investigate engaging since it reveals how mutations in FUS could have even some-more widespread consequences than formerly thought. This is unchanging with a aggressive, early conflict ALS caused by several FUS mutations, including R495X. Pandey combined that a authors’ anticipating that a C. elegans homolog of FUS facilitates miRNA silencing indicates a pathway is rarely conserved. On a flip side, Goldberg remarkable that it is harder to explain engine neuron selectivity with a distress of this sort.

Given a duds of FUS functions, what competence this new one minister to ALD/FTD? “Of march a dream would be to brand a singular target, though we have all these functions. It is rarely frustrating from a medical perspective,” pronounced Goldberg. Wang agreed, though added, “It is critical to know a biology to eventually make corrections.” A deeper simple bargain could also lead to a find of biomarkers, he said.

Wang wants to demeanour for identical functions in other disease-related RNA-binding proteins. A claimant is TDP-43, that is also concerned in miRNA production. Pandey would like to see either other FUS mutations, such as P525L, likewise impact miRNA activity. Like R495X, P525L causes a serious form of ALS with large cytoplasmic FUS accumulation. He hopes a fatalistic work reported here can be replicated in engine neurons subsequent from patient-induced pluripotent branch cells and postmortem samples.

Featured Paper

Zhang T, Wu YC, Mullane P, Ji YJ, Liu H, He L, Arora A, Hwang HY, Alessi AF, Niaki AG, Periz G, Guo L, Wang H, Elkayam E, Joshua-Tor L, Myong S, Kim JK, Shorter J, Ong SE, Leung AK, Wang J. FUS Regulates Activity of MicroRNA-Mediated Gene Silencing. Molecular Cell 69, 1-15, Mar 1, 2018

References

Dini Modigliani S, Morlando M, Errichelli L, Sabatelli M, Bozzoni I. An ALS-associated turn in a FUS 3′-UTR disrupts a microRNA-FUS regulatory circuitry. Nat Commun. 2014 Jul 9;5:4335. PubMed.

Morlando M, Dini Modigliani S, Torrelli G, Rosa A, Di Carlo V, Caffarelli E, Bozzoni I. FUS stimulates microRNA biogenesis by facilitating co-transcriptional Drosha recruitment. EMBO J. 2012 Dec 12;31(24):4502-10. PubMed.

Further Reading

Rinchetti P, Rizzuti M, Faravelli I, Corti S. MicroRNA Metabolism and Dysregulation in Amyotrophic Lateral Sclerosis. Mol Neurobiol. 2017 Apr 18; PubMed.

Deng H, Gao K, Jankovic J. The purpose of FUS gene variants in neurodegenerative diseases. Nat Rev Neurol. 2014 Jun;10(6):337-48. Epub 2014 May 20 PubMed.

Capauto D, Colantoni A, Lu L, Santini T, Peruzzi G, Biscarini S, Morlando M, Shneider NA, Caffarelli E, Laneve P, Bozzoni I. A Regulatory Circuitry Between Gria2, miR-409, and miR-495 Is Affected by ALS FUS Mutation in ESC-Derived Motor Neurons. Mol Neurobiol. 2018 Feb 12. PubMed.


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