2. Academic Validation
  3. TBK1 Induces the Formation of Optineurin Filaments That Condensate with Polyubiquitin and LC3 for Cargo Sequestration

TBK1 Induces the Formation of Optineurin Filaments That Condensate with Polyubiquitin and LC3 for Cargo Sequestration

  • Adv Sci (Weinh). 2025 Dec 17:e09927. doi: 10.1002/advs.202509927.
Maria G Herrera 1 2,  Lena Kühn 1,  Lisa Jungbluth 3,  Verian Bader 1 4,  Laura J Krause 1,  David Kartte 3,  Elias Adriaenssens 5 6,  Sascha Martens 5 6,  Jörg Tatzelt 4 7,  Carsten Sachse 3 8,  Konstanze F Winklhofer 1 7
Affiliations

Affiliations

  • 1 Department Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany.
  • 2 Faculty of Exact and Natural Sciences, Institute of Biosciences, Biotechnology and Translational Biology (iB3), University of Buenos Aires, Intendente Güiraldes 2160, Ciudad Universitaria, Buenos Aires, C1428EGA, Argentina.
  • 3 Ernst-Ruska Centre for Microscopy and Spectroscopy with Electrons, ER-C-3/Structural Biology, Forschungszentrum Jülich, 52425, Jülich, Germany.
  • 4 Department Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, 44801, Bochum, Germany.
  • 5 Max Perutz Labs, Vienna Biocenter Campus (VBC), Vienna, 1030, Austria.
  • 6 Max Perutz Labs, Department of Biochemistry and Cell Biology, University of Vienna, Vienna, 1030, Austria.
  • 7 Cluster of Excellence RESOLV, Ruhr University Bochum, 44801, Bochum, Germany.
  • 8 Department of Biology, Heinrich Heine University, Universitätsstr. 1, 40225, Düsseldorf, Germany.
PMID: 41405403 DOI: 10.1002/advs.202509927
Abstract

Optineurin is an Autophagy receptor that plays an important role in the selective degradation of mitochondria, protein aggregates, and intracellular pathogens. It recognizes ubiquitylated cargo by its ubiquitin-binding in ABIN and NEMO (UBAN) domain and recruits the autophagic machinery through its LC3-interacting region (LIR) domain. Phosphorylation of Optineurin by TANK-binding kinase 1 (TBK1) increases the binding of Optineurin to both ubiquitin chains and lipidated microtubule-associated protein light chain 3 (LC3). Optineurin has been reported to form foci at ubiquitylated cargo, but the underlying mechanism and how these foci are linked to selective Autophagy has remained largely unknown. This study shows that phosphorylation of Optineurin by TBK1 induces the formation of filaments that phase separate upon binding to linear polyubiquitin. LC3 anchored to unilamellar vesicles co-partitions into Optineurin/polyubiquitin condensates, resulting in the local deformation of the vesicle membrane. Thus, the condensation of filamentous Optineurin with ubiquitylated cargo promotes the nucleation of cargo and its subsequent alignment with LC3-positive nascent autophagosomes, suggesting that co-condensation processes ensure directionality in selective Autophagy.

Keywords

Optineurin; TBK1; autophagy; phase separation; ubiquitin.

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