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<p>The microtubule (MT) association of protein Tau is decreased upon phosphorylation. Increased levels of phosphorylated Tau in the cytosol pose the risk of pathological aggregation, as observed in neurodegenerative diseases. We show that binding of 14-3-3ζ enhances cytosolic Tau solubility by promoting phosphorylated Tau removal from MTs, while simultaneously inhibiting Tau aggregation both directly and indirectly via suppression of condensate formation. These 14-3-3ζ activities depend on site-specific binding of 14-3-3 to Tau phosphorylated at S214 and S324. At sub-stoichiometric 14-3-3ζ concentrations, or in the presence of other 14-3-3ζ binding partners, multivalent electrostatic interactions promote Tau:14-3-3ζ co-condensation, offering a phosphorylation-independent mode of Tau-14-3-3ζ interactions. Given the high abundance of 14-3-3 proteins in the brain, 14-3-3 binding could provide efficient multi-modal chaperoning activity for Tau in the healthy brain and be important for preventing Tau aggregation in disease.</p><p></p>

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Stoichiometric 14-3-3ζ binding promotes phospho-Tau microtubule dissociation and reduces aggregation and condensation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月31日

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  • Janine Hochmair,
  • Maxime C. M. van den Oetelaar,
  • Leandre Ravatt,
  • Lisa Diez,
  • Lenne J. M. Lemmens,
  • Renata Ponce-Lina,
  • Rithika Sankar,
  • Maximilian Franck,
  • Gesa Nolte,
  • Ekaterina Semenova,
  • Satabdee Mohapatra,
  • Christian Ottmann,
  • Luc Brunsveld,
  • Susanne Wegmann

摘要

The microtubule (MT) association of protein Tau is decreased upon phosphorylation. Increased levels of phosphorylated Tau in the cytosol pose the risk of pathological aggregation, as observed in neurodegenerative diseases. We show that binding of 14-3-3ζ enhances cytosolic Tau solubility by promoting phosphorylated Tau removal from MTs, while simultaneously inhibiting Tau aggregation both directly and indirectly via suppression of condensate formation. These 14-3-3ζ activities depend on site-specific binding of 14-3-3 to Tau phosphorylated at S214 and S324. At sub-stoichiometric 14-3-3ζ concentrations, or in the presence of other 14-3-3ζ binding partners, multivalent electrostatic interactions promote Tau:14-3-3ζ co-condensation, offering a phosphorylation-independent mode of Tau-14-3-3ζ interactions. Given the high abundance of 14-3-3 proteins in the brain, 14-3-3 binding could provide efficient multi-modal chaperoning activity for Tau in the healthy brain and be important for preventing Tau aggregation in disease.