NEMO reshapes the protein aggregate interface and promotes aggrephagy by co-condensation with p62

Furthmann, N.; Angersbach, L.; Bader, V.; Blusch, A.; Goel, S.; Sanchez-Vicente, A.; Krause, L. J.; 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.; Glatzel, M.; Hartl, F.-U.; Nakamura, K.; Christine, C.; Huang, E. J.; Tatzelt, J.; Winklhofer, K. F.

doi:10.1101/2023.06.05.543428

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bioRxiv · 10.1101/2023.06.05.543428

NEMO reshapes the protein aggregate interface and promotes aggrephagy by co-condensation with p62

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Abstract

NEMO is a ubiquitin-binding protein which regulates canonical NF-{kappa}B pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identified an NF-{kappa}B-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 gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including -synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at -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.

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Furthmann, N., Angersbach, L., Bader, V., Blusch, A., Goel, S., Sanchez-Vicente, A., Krause, L. J., 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., Glatzel, M., Hartl, F.-U., Nakamura, K., Christine, C., Huang, E. J., Tatzelt, J., Winklhofer, K. F.. 2023-06-06. NEMO reshapes the protein aggregate interface and promotes aggrephagy by co-condensation with p62. https://doi.org/10.1101/2023.06.05.543428

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