Sex-specific perturbations of neuronal development caused by mutations in the autism risk gene DDX3X DOI Open Access

Adele Mossa,

Lauren Dierdorff,

Jerónimo Lukin

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

ABSTRACT DDX3X is an X-linked RNA helicases that escapes X chromosome inactivation and expressed at higher levels in female brains. Mutations are associated with intellectual disability (ID) autism spectrum disorder (ASD) predominantly identified females. Using cellular mouse models, we show Ddx3x mediates sexual dimorphisms brain development a molecular, cellular, behavioral level. During cortical neuronal development, sustains female-biased signature of enhanced ribosomal biogenesis mRNA translation. Female neurons display proteins larger nucleoli, these sex obliterated by loss. regulates dendritic outgrowth sex- dose-dependent manner both male neurons, spine only neurons. Further, ablating conditionally forebrain sufficient to yield sex-specific changes developmental outcomes motor function. Together, findings pose as mediator differentiation during neurodevelopment open new avenues understand differences health disease.

Language: Английский

Formation, function, and pathology of RNP granules DOI Creative Commons
Nina Ripin,

Roy Parker

Cell, Journal Year: 2023, Volume and Issue: 186(22), P. 4737 - 4756

Published: Oct. 1, 2023

Language: Английский

Citations

80
The Story of RNA Unfolded: The Molecular Function of DEAD- and DExH-Box ATPases and Their Complex Relationship with Membraneless Organelles DOI
Kerstin Dörner, Maria Hondele

Annual Review of Biochemistry, Journal Year: 2024, Volume and Issue: 93(1), P. 79 - 108

Published: April 10, 2024

DEAD- and DExH-box ATPases (DDX/DHXs) are abundant highly conserved cellular enzymes ubiquitously involved in RNA processing. By remodeling RNA–RNA RNA–protein interactions, they often function as gatekeepers that control the progression of diverse maturation steps. Intriguingly, most DDX/DHXs localize to membraneless organelles (MLOs) such nucleoli, nuclear speckles, stress granules, or processing bodies. Recent findings suggest not only localization MLOs can promote interaction between their targets but also key regulators MLO formation turnover through condensation ATPase activity.In this review, we describe molecular ribosome biogenesis, messenger splicing, export, translation, storage decay well association with prominent MLOs. We discuss how enzymatic is linked DDX/DHX condensation, accumulation ribonucleoprotein particles dynamics. Future research will reveal these processes orchestrate life cycle space time.

Language: Английский

Citations

9
The variant landscape and function of DDX3X in cancer and neurodevelopmental disorders DOI Creative Commons
Margaret Gadek, Elliott H. Sherr, Stephen N. Floor

et al.

Trends in Molecular Medicine, Journal Year: 2023, Volume and Issue: 29(9), P. 726 - 739

Published: July 6, 2023

RNA molecules rely on proteins across their life cycle. DDX3X encodes an X-linked DEAD-box helicase with a Y-linked paralog, DDX3Y. is central to the cycle and implicated in many conditions, including cancer neurodevelopmental disorder syndrome. DDX3X-linked conditions often exhibit sex differences, possibly due differences between expression or function of X- paralogs DDX3X-related diseases have different mutational landscapes, indicating roles DDX3X. Understanding role normal disease states will inform understanding disease. We review DDX3Y, discuss how mutation type bias contribute human involving DDX3X, possible DDX3X-targeting treatments.

Language: Английский

Citations

21
Biomolecular condensates: Formation mechanisms, biological functions, and therapeutic targets DOI Creative Commons
Xin Niu, Lei Zhang, Yuchen Wu

et al.

MedComm, Journal Year: 2023, Volume and Issue: 4(2)

Published: Feb. 28, 2023

Abstract Biomolecular condensates are cellular structures composed of membraneless assemblies comprising proteins or nucleic acids. The formation these requires components to change from a state solubility separation the surrounding environment by undergoing phase transition and condensation. Over past decade, it has become widely appreciated that biomolecular ubiquitous in eukaryotic cells play vital role physiological pathological processes. These may provide promising targets for clinic research. Recently, series processes have been found associated with dysfunction condensates, range methods demonstrated modulate condensates. A more extensive description is urgently needed development novel therapies. In this review, we summarized current understanding molecular mechanisms their formation. Moreover, reviewed functions therapeutic diseases. We further highlighted available regulatory methods, discussed significance challenges targeting Reviewing latest developments condensate research could be essential translating our knowledge on use clinical strategies.

Language: Английский

Citations

20
The RNA helicase DDX39A binds a conserved structure in chikungunya virus RNA to control infection DOI Creative Commons
Iulia Tapescu, Frances Taschuk, Swechha M. Pokharel

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(22), P. 4174 - 4189.e7

Published: Nov. 1, 2023

Alphaviruses are a large group of re-emerging arthropod-borne RNA viruses. The compact viral genomes harbor diverse structures that facilitate replication. These can be recognized by antiviral cellular RNA-binding proteins, including DExD-box (DDX) helicases, bind RNAs to control infection. full spectrum DDXs and the remain unclear. Genetic screening identified DDX39A as against alphavirus chikungunya virus (CHIKV) other medically relevant alphaviruses. Upon infection, predominantly nuclear accumulates in cytoplasm inhibiting replication, independent canonical interferon pathway. Biochemically, binds CHIKV genomic RNA, interacting with 5′ conserved sequence element (5′CSE), which is essential for activity DDX39A. Altogether, relocalization binding structural attenuates revealing previously unknown layer

Language: Английский

Citations

19
Stress granule-localized USP8 potentiates cGAS-mediated type I interferonopathies through deubiquitination of DDX3X DOI Creative Commons
Xuejing Zhang, Lulu Han, Jinxiu Hou

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(6), P. 114248 - 114248

Published: May 24, 2024

Cyclic GMP-AMP synthase (cGAS) undergoes liquid-liquid phase separation (LLPS) to trigger downstream signaling upon double-stranded DNA (dsDNA) stimulation, and the condensed cGAS colocalizes with stress granules (SGs). However, molecular mechanism underlying modulation of activation by SGs remains elusive. In this study, we show that USP8 is localized dsDNA stimulation potentiates cGAS-stimulator interferon genes (STING) signaling. A inhibitor ameliorates pathological inflammation in Trex1−/− mice. Systemic lupus erythematosus (SLE) databases indicate a positive correlation between expression SLE. Mechanistic study shows SG protein DDX3X promotes manner dependent on its intrinsic LLPS. cleaves K27-linked ubiquitin chains from intrinsically disordered region (IDR) enhance condensation. conclusion, demonstrate catalyzes deubiquitination facilitate condensation inhibiting promising strategy for alleviating cGAS-mediated autoimmune diseases.

Language: Английский

Citations

7
A comprehensive review on DDX3X liquid phase condensation in health and neurodevelopmental disorders DOI
Ivan Rosa e Silva, Juliana Helena Costa Smetana, Juliana Ferreira de Oliveira

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 259, P. 129330 - 129330

Published: Jan. 11, 2024

Language: Английский

Citations

6
Phase separation-mediated biomolecular condensates and their relationship to tumor DOI Creative Commons
Xi Wang, Jiameng Liu, Chaoming Mao

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 21, 2024

Abstract Phase separation is a cellular phenomenon where macromolecules aggregate or segregate, giving rise to biomolecular condensates resembling "droplets" and forming distinct, membrane-free compartments. This process pervasive in biological cells, contributing various essential functions. However, when phase goes awry, leading abnormal molecular aggregation, it can become driving factor the development of diseases, including tumor. Recent investigations have unveiled intricate connection between dysregulated tumor pathogenesis, highlighting its potential as novel therapeutic target. article provides an overview recent research, with particular emphasis on role tumor, implications, outlines avenues for further exploration this intriguing field.

Language: Английский

Citations

5
DDX RNA helicases: key players in cellular homeostasis and innate antiviral immunity DOI Creative Commons
Iulia Tapescu, Sara Cherry

Journal of Virology, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 30, 2024

RNA helicases are integral in metabolism, performing important roles cellular homeostasis and stress responses. In particular, the DExD/H-box (DDX) helicase family possesses a conserved catalytic core that binds structural features rather than specific sequences targets. DDXs have critical all aspects of metabolism including ribosome biogenesis, translation, export, stability. Importantly, functional specialization within this arises from divergent N C termini is driven at least part by gene duplications with 18 42 human having paralogs. addition to their key homeostatic control RNA, these factors virus infection. The canonical RIG-I-like receptors (RLRs) play pivotal cytoplasmic sensing viral structures, inducing antiviral expression. Additional function as sensors or regulators, further diversifying innate immune defense arsenal. Moreover, some been coopted viruses facilitate replication. Altogether, DDX exhibit specificity, playing intricate host defense. This review will discuss mechanisms which recognize diverse structures RNAs, how impacts processing

Language: Английский

Citations

5
DEAD-box ATPases as regulators of biomolecular condensates and membrane-less organelles DOI
Daan Overwijn, Maria Hondele

Trends in Biochemical Sciences, Journal Year: 2022, Volume and Issue: 48(3), P. 244 - 258

Published: Nov. 4, 2022

Language: Английский

Citations

20