Journal Article

FZJ-2024-00271

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62

Furthmann, N. ; Bader, V. ; Angersbach, L. ; Blusch, A. ; Goel, S. ; Sánchez-Vicente, A. ; Krause, L. J. ; Chaban, S. A. ; Grover, P. ; Trinkaus, V. A. ; van Well, E. M. ; Jaugstetter, M. ; Tschulik, K. ; Damgaard, R. B. ; Saft, C. ; Ellrichmann, G. ; Gold, R. ; Koch, A. ; Englert, B. ; Westenberger, A. ; Klein, C. ; Jungbluth, L.FZJ* ; Sachse, C.FZJ* ; Behrends, C. ; Glatzel, M. ; Hartl, F. U. ; Nakamura, K. ; Christine, C. W. ; Huang, E. J. ; Tatzelt, J. ; Winklhofer, K. F. (Corresponding author)

2023
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-023-44033-0  doi:10.34734/FZJ-2024-00271

Abstract: NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathwayactivation in innate immune signaling, cell death regulation and host-pathogeninteractions. Here we identify an NF-κB-independent function of NEMO inproteostasis regulation by promoting autophagosomal clearance of proteinaggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxicstress and are vulnerable to proteostasis challenges. Moreover, apatient with a mutation in the NEMO-encoding IKBKG gene resulting indefective binding of NEMO to linear ubiquitin chains, developed a widespreadmixed brain proteinopathy, including α-synuclein, tau and TDP-43 pathology.NEMO amplifies linear ubiquitylation at α-synuclein aggregates and promotesthe local concentration of p62 into foci. In vitro, NEMO lowers the thresholdconcentrations required for ubiquitin-dependent phase transition of p62. Insummary, NEMO reshapes the aggregate surface for efficient autophagosomalclearancebyprovidingamobilephase at theaggregate interphase favoringcocondensationwith p62.

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Contributing Institute(s):

1. Strukturbiologie (ER-C-3)
2. Zelluläre Strukturbiologie (IBI-6)

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)

Appears in the scientific report 2023

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