Specific catalytically impaired DDX3X mutants form sexually dimorphic hollow condensates

Michael C. Owens, Hui Shen, Amber Yanas, Maria Saraí Mendoza-Figueroa, Ellen Lavorando, Xiaoyu Wei, Him Shweta, Hsin-Yao Tang, Yale E. Goldman () and Kathy Fange Liu ()
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Michael C. Owens: University of Pennsylvania
Hui Shen: University of Pennsylvania
Amber Yanas: University of Pennsylvania
Maria Saraí Mendoza-Figueroa: University of Pennsylvania
Ellen Lavorando: University of Pennsylvania
Xiaoyu Wei: University of Pennsylvania
Him Shweta: University of Pennsylvania
Hsin-Yao Tang: The Wistar Institute
Yale E. Goldman: University of Pennsylvania
Kathy Fange Liu: University of Pennsylvania

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Mutations in the RNA helicase DDX3X, implicated in various cancers and neurodevelopmental disorders, often impair RNA unwinding and translation. However, the mechanisms underlying the impairment and the differential interactions of DDX3X mutants with wild-type (WT) X-linked DDX3X and Y-linked homolog DDX3Y remain elusive. This study reveals that specific DDX3X mutants more frequently found in disease form distinct hollow condensates in cells. Using a combined structural, biochemical, and single-molecule microscopy study, we show that reduced ATPase and RNA release activities contribute to condensate formation and these catalytic deficits result from inhibiting the catalytic cycle at multiple steps. Proteomic investigations further demonstrate that these hollow condensates sequester WT DDX3X/DDX3Y and other proteins crucial for diverse signaling pathways. WT DDX3X enhances the dynamics of heterogeneous mutant/WT hollow condensates more effectively than DDX3Y. These findings offer valuable insights into the catalytic defects of specific DDX3X mutants and their differential interactions with wild-type DDX3X and DDX3Y, potentially explaining sex biases in disease.

Date: 2024
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DOI: 10.1038/s41467-024-53636-0

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