LLPS of FXR1 drives spermiogenesis by activating translation of stored mRNAs

Kang, Jun-Yan; Wen, Ze; Pan, Duo; Zhang, Yuhan; Li, Qing; Zhong, Ai; Yu, Xinghai; Wu, Yichen; Chen, Yu; Zhang, Xiangzheng; Kou, Peng-Cheng; Geng, Junlan; Wang, Yingyi; Hua, Min-Min; Zong, Ruiting; Li, Biao; Shi, Huijuan; Li, Dangsheng; Fu, Xiang‐Dong; Li, Jinsong; Nelson, David L.; Guo, Xuejiang; Zhou, Yu; Gou, Lantu; Huang, Ying; Liu, Mofang

doi:10.1126/science.abj6647

Cited by 105 publications

(64 citation statements)

References 63 publications

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“…7b ) which were reported to facilitate translation initiation during spermatogenesis 63 , 64 . A recent study showed that FXR1 also promotes translation together with EIF4G3 and PABPC1 to drive spermiogenesis 65 . EIF4G3 has also been shown to be required for male fertility, and its deficiency causes failed entry to the meiotic metaphase during spermatogenesis, defects also observed in PRRC2A-null spermatocytes 64 .…”

Section: Resultsmentioning

confidence: 99%

The m6A reader PRRC2A is essential for meiosis I completion during spermatogenesis

et al. 2023

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N6-methyladenosine (m6A) and its reader proteins YTHDC1, YTHDC2, and YTHDF2 have been shown to exert essential functions during spermatogenesis. However, much remains unknown about m6A regulation mechanisms and the functions of specific readers during the meiotic cell cycle. Here, we show that the m6A reader Proline rich coiled-coil 2A (PRRC2A) is essential for male fertility. Germ cell-specific knockout of Prrc2a causes XY asynapsis and impaired meiotic sex chromosome inactivation in late-prophase spermatocytes. Moreover, PRRC2A-null spermatocytes exhibit delayed metaphase entry, chromosome misalignment, and spindle disorganization at metaphase I and are finally arrested at this stage. Sequencing data reveal that PRRC2A decreases the RNA abundance or improves the translation efficiency of targeting transcripts. Specifically, PRRC2A recognizes spermatogonia-specific transcripts and downregulates their RNA abundance to maintain the spermatocyte expression pattern during the meiosis prophase. For genes involved in meiotic cell division, PRRC2A improves the translation efficiency of their transcripts. Further, co-immunoprecipitation data show that PRRC2A interacts with several proteins regulating mRNA metabolism or translation (YBX1, YBX2, PABPC1, FXR1, and EIF4G3). Our study reveals post-transcriptional functions of PRRC2A and demonstrates its critical role in the completion of meiosis I in spermatogenesis.

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Section: Resultsmentioning

confidence: 99%

The m6A reader PRRC2A is essential for meiosis I completion during spermatogenesis

et al. 2023

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“…To reach conditions that can most accurately capture the dynamics of translation, diverse UAS promoters together with a variety of available Gal4 drivers should be tested depending on the tissue of interest and the expression level of the tagged gene. Studies on mRNA localization and local translation have speculated that different mRNAs species may be translationally co-regulated [56][57][58] . To obtain independent translational readouts of different mRNA simultaneously, one can combine orthogonal tagging systems.…”

Section: Discussionmentioning

confidence: 99%

Boosting the toolbox for live imaging of translation

Bellec

Chen²,

Dhayni

et al. 2023

Preprint

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Live imaging of translation based on a tag recognition by a single chain antibody is a powerful technique to assess the fine tuning of translation regulation in living cells. However, especially in a multicellular organism, this approach is challenging and requires optimization in terms of expression level and detection sensitivity of the system. Here, we improved existing fluorescent tools and developed new ones to image and quantify nascent translation in the living Drosophila embryo and in mammalian cells. We tested and characterized five different Green Fluorescent Protein variants fused to the single chain fragment variable (scFv) and uncover photobleaching, aggregation and intensity disparities. Using different strengths of germline and somatic drivers, we determined that the availability of the scFv is critical in order to detect translation throughout development. Finally, we introduced a new translation imaging method, based on a nanobody/tag system, named ALFA_array, allowing the sensitive and simultaneous detection of the translation of several distinct mRNA species.

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“…Intriguingly, it was recently discovered that liquid-liquid phase separation of RBPs can also promote translation of bound mRNAs. The RBP Fragile X Mental Retardation Syndrome-Related Protein 1 (FXR1) was shown to actively recruit and promote translation of its target mRNAs after undergoing LLPS ( Kang et al, 2022 ). It is conceivable that DDX3X may possess a similar function.…”

Section: Translation Regulation By Ddx3x and Its Physiological Conseq...mentioning

confidence: 99%

The human DEAD-box helicase DDX3X as a regulator of mRNA translation

Ryan

Schröder

2022

Front. Cell Dev. Biol.

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The human DEAD-box protein DDX3X is an RNA remodelling enzyme that has been implicated in various aspects of RNA metabolism. In addition, like many DEAD-box proteins, it has non-conventional functions that are independent of its enzymatic activity, e.g., DDX3X acts as an adaptor molecule in innate immune signalling pathways. DDX3X has been linked to several human diseases. For example, somatic mutations in DDX3X were identified in various human cancers, and de novo germline mutations cause a neurodevelopmental condition now termed ‘DDX3X syndrome’. DDX3X is also an important host factor in many different viral infections, where it can have pro-or anti-viral effects depending on the specific virus. The regulation of translation initiation for specific mRNA transcripts is likely a central cellular function of DDX3X, yet many questions regarding its exact targets and mechanisms of action remain unanswered. In this review, we explore the current knowledge about DDX3X’s physiological RNA targets and summarise its interactions with the translation machinery. A role for DDX3X in translational reprogramming during cellular stress is emerging, where it may be involved in the regulation of stress granule formation and in mediating non-canonical translation initiation. Finally, we also discuss the role of DDX3X-mediated translation regulation during viral infections. Dysregulation of DDX3X’s function in mRNA translation likely contributes to its involvement in disease pathophysiology. Thus, a better understanding of its exact mechanisms for regulating translation of specific mRNA targets is important, so that we can potentially develop therapeutic strategies for overcoming the negative effects of its dysregulation.

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LLPS of FXR1 drives spermiogenesis by activating translation of stored mRNAs

Cited by 105 publications

References 63 publications

The m6A reader PRRC2A is essential for meiosis I completion during spermatogenesis

The m6A reader PRRC2A is essential for meiosis I completion during spermatogenesis

Boosting the toolbox for live imaging of translation

The human DEAD-box helicase DDX3X as a regulator of mRNA translation

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