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<p>In many viruses, intrinsically disordered proteins (IDPs) drive the formation of replicative organelles via liquid–liquid phase separation (LLPS). In species A rotaviruses, the disordered protein NSP5 forms condensates with NSP2, but its high sequence diversity raises questions about whether this mechanism is conserved across strains. Using a machine learning approach, we show that NSP5 variants differ significantly in LLPS propensity. We engineered an NSP5 variant with features derived from strains with low-LLPS propensity (low-LLPS). Despite lacking the ability to phase separate in vitro unless phosphorylated, this variant nevertheless supported condensate formation and viral replication in cells. We found that low-LLPS variants require phosphorylation to nucleate phase separation, whereas high-LLPS variants do not, suggesting distinct nucleation mechanisms between viral strains. Hydrogen–deuterium exchange mass spectrometry revealed a phosphorylation-driven allosteric switch that alters NSP2 interactions depending on the NSP5 variant. These findings suggest that phosphorylation plays a context-dependent role in condensate formation, tuning NSP5-NSP2 interactions in a strain-specific manner and highlighting the mechanistic diversity underpinning replicative organelle formation among viral strains.</p>

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Phosphorylation tunes strain-specific protein condensation during rotavirus replication organelle assembly

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Julia Acker,
  • Xinyu Wang,
  • Alonso J Pardal,
  • Daniel Desirò,
  • Tanushree Agarwal,
  • Alice Colyer,
  • Aidan Tollervey,
  • Rob Scrutton,
  • Cyril Haller,
  • Lee Sherry,
  • Kadi L Saar,
  • Ksenia Fominykh,
  • Margaret L L Y Johncock,
  • Sai Hou Chong,
  • Rosie Murray,
  • Jamie Terry,
  • Jeremy D Schmit,
  • Antonio N Calabrese,
  • Tuomas P J Knowles,
  • Alexander Borodavka

摘要

In many viruses, intrinsically disordered proteins (IDPs) drive the formation of replicative organelles via liquid–liquid phase separation (LLPS). In species A rotaviruses, the disordered protein NSP5 forms condensates with NSP2, but its high sequence diversity raises questions about whether this mechanism is conserved across strains. Using a machine learning approach, we show that NSP5 variants differ significantly in LLPS propensity. We engineered an NSP5 variant with features derived from strains with low-LLPS propensity (low-LLPS). Despite lacking the ability to phase separate in vitro unless phosphorylated, this variant nevertheless supported condensate formation and viral replication in cells. We found that low-LLPS variants require phosphorylation to nucleate phase separation, whereas high-LLPS variants do not, suggesting distinct nucleation mechanisms between viral strains. Hydrogen–deuterium exchange mass spectrometry revealed a phosphorylation-driven allosteric switch that alters NSP2 interactions depending on the NSP5 variant. These findings suggest that phosphorylation plays a context-dependent role in condensate formation, tuning NSP5-NSP2 interactions in a strain-specific manner and highlighting the mechanistic diversity underpinning replicative organelle formation among viral strains.