Multivalent ubiquitin recognition regulates multiple stages of Tau self-assembly
- 1KU Leuven
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 the canonical hydrophobic patch of ubiquitin, 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.
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BibTeX
@misc{muwonge2026multivalent,
title = {{Multivalent ubiquitin recognition regulates multiple stages of Tau self-assembly}},
author = {K. Muwonge and L. F. Duran-Armenta and T. Lazar and A. Meszaros and A. Volkov and A. Navarro and C. Marino-Buslje and M. L. Fernandez and G. J. Gutierrez and N. M. Kanaan and R. Loris and P. Tompa},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.09.757857},
url = {https://www.biorxiv.org/content/10.64898/2026.10.09.757857v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Multivalent ubiquitin recognition regulates multiple stages of Tau self-assembly
AU - K. Muwonge
AU - L. F. Duran-Armenta
AU - T. Lazar
AU - A. Meszaros
AU - A. Volkov
AU - A. Navarro
AU - C. Marino-Buslje
AU - M. L. Fernandez
AU - G. J. Gutierrez
AU - N. M. Kanaan
AU - R. Loris
AU - P. Tompa
PY - 2026
DA - 2026/10/09
PB - bioRxiv
DO - 10.64898/2026.10.09.757857
UR - https://www.biorxiv.org/content/10.64898/2026.10.09.757857v1
AB - 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 the canonical hydrophobic patch of ubiquitin, 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.
ER -