Multivalent ubiquitin recognition regulates multiple stages of Tau self-assembly
Year: 2026
Type: preprint
Abstract: Liquid-liquid phase separation (LLPS) has emerged as an important intermediate in the pathological self-assembly of Tau, yet the molecular mechanisms that regulate this process remain incompletely understood. Although ubiquitin is a prominent component of pathological inclusions in tauopathies and other neurodegenerative diseases, its presence has largely been linked to targeting aberrant proteins for proteasomal or autophagic clearance. Here, we identify Tau as a ubiquitin-binding protein and demonstrate that multivalent, non-covalent ubiquitin recognition regulates multiple stages of Tau self-assembly. Biochemical, biophysical, structural, and computational analyses identified four ubiquitin-binding elements within the Tau microtubule-binding repeat region that engage ubiquitin’s canonical hydrophobic patch, providing a structural basis for multivalent recognition of mono- and poly-ubiquitin species. Functionally, mono- and poly-ubiquitin suppress Tau condensate formation while enhancing the liquid-like properties of condensates that persist. In contrast, mono-ubiquitin selectively enhances aggregation of the disease-linked Tau-P301L variant under conditions without detectable LLPS, demonstrating that ubiquitin exerts distinct effects depending on the molecular context and stage of Tau self-assembly. Together, these findings establish non-covalent ubiquitin recognition as a previously unrecognized mechanism regulating Tau phase behavior and aggregation. More broadly, they expand the role of ubiquitin beyond protein quality control, with ubiquitin architecture providing an additional layer of regulation over Tau condensate formation, dynamics, maturation, and aggregation.
Institutions: Vrije Universiteit Brussel, Vlaams Instituut voor Biotechnologie, VIB-VUB Center for Structural Biology, Fundación Instituto Leloir, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Michigan State University, National Institute of Oncology, Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7221512953