NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62.

Abstract

NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-κB-independent function of NEMO in proteostasis regulation by promoting autophagosomal clearance of protein aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress and are vulnerable to proteostasis challenges. Moreover, a patient with a mutation in the NEMO-encoding IKBKG gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including α-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at α-synuclein aggregates and promotes the local concentration of p62 into foci. In vitro, NEMO lowers the threshold concentrations required for ubiquitin-dependent phase transition of p62. In summary, NEMO reshapes the aggregate surface for efficient autophagosomal clearance by providing a mobile phase at the aggregate interphase favoring co-condensation with p62.

• Authors: Nikolas Furthmann, Verian Bader, Lena Angersbach, Alina Blusch, Simran Goel, Ana Sánchez-Vicente, Laura J Krause, Sarah A Chaban, Prerna Grover, Victoria A Trinkaus, Eva M van Well, Maximilian Jaugstetter, Kristina Tschulik, Rune Busk Damgaard, Carsten Saft, Gisa Ellrichmann, Ralf Gold, Arend Koch, Benjamin Englert, Ana Westenberger, Christine Klein, Lisa Jungbluth, Carsten Sachse, Christian Behrends, Markus Glatzel, F Ulrich Hartl, Ken Nakamura, Chadwick W Christine, Eric J Huang, Jörg Tatzelt, Konstanze F Winklhofer
• Journal: Nature communications (Nat Commun) Vol. 14 Issue 1 Pg. 8368 (Dec 19 2023) ISSN: 2041-1723 [Electronic] England
• PMID: 38114471 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s).

Chemical References

• NF-kappa B
• I-kappa B Kinase
• alpha-Synuclein
• Ubiquitin
• IKBKG protein, human

Topics

• Humans
• NF-kappa B (metabolism)
• I-kappa B Kinase (genetics, metabolism)
• alpha-Synuclein (genetics)
• Ubiquitin (metabolism)
• Autophagy (genetics)