Journal Article

FZJ-2026-00403

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png TBK1 Induces the Formation of Optineurin Filaments That Condensate with Polyubiquitin and LC3 for Cargo Sequestration

Herrera, M. G. ; Kühn, L. ; Jungbluth, L. ; Bader, V. ; Krause, L. J. ; Kartte, D. ; Adriaenssens, E. ; Martens, S. ; Tatzelt, J. ; Sachse, C.FZJ* ; Winklhofer, K. F. (Corresponding author)

2025
Wiley-VCH Weinheim

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Please use a persistent id in citations: 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.

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Contributing Institute(s):

1. Strukturbiologie (ER-C-3)

Research Program(s):

1. 5352 - Understanding the Functionality of Soft Matter and Biomolecular Systems (POF4-535) (POF4-535)
2. 5241 - Molecular Information Processing in Cellular Systems (POF4-524) (POF4-524)

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