LUBAC assembles a signaling platform at mitochondria for signal amplification and shuttling of NF-ĸB to the nucleus

Wu, Z.; Berlemann, L. A.; Bader, V.; Sehr, D. A.; Eilers, E.; Covallero, A.; Meschede, J.; Angersbach, L.; Showkat, C.; Michaelis, J. B.; Muench, C.; Rieger, B.; Namgaladze, D.; Herrera, M. G.; Fiesel, F. C.; Springer, W.; Mendes, M.; Stepien, J.; Barkovits, K.; Marcus, K.; Sickmann, A.; Dittmar, G.; Busch, K. B.; Riedel, D.; Brini, M.; Tatzelt, J.; Cali, T.; Winklhofer, K. F.

doi:10.1101/2022.05.27.493704

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bioRxiv · 10.1101/2022.05.27.493704

LUBAC assembles a signaling platform at mitochondria for signal amplification and shuttling of NF-ĸB to the nucleus

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Abstract

Mitochondria are increasingly recognized as cellular hubs to orchestrate signaling pathways that regulate metabolism, redox homeostasis, and cell fate decisions. Recent research revealed a role of mitochondria also in innate immune signaling, however, the mechanisms of how mitochondria affect signal transduction are poorly understood. Here we show that the NF-B pathway activated by TNF employs mitochondria as a platform for signal amplification and shuttling of activated NF-B to the nucleus. TNF induces the recruitment of HOIP, the catalytic component of the linear ubiquitin chain assembly complex (LUBAC), and its substrate NEMO to the outer mitochondrial membrane, where M1- and K63-linked ubiquitin chains are generated. NF-B is locally activated and transported to the nucleus by mitochondria, resulting in an increase in mitochondria-nucleus contact sites in a HOIP-dependent manner. Notably, TNF-induced stabilization of the mitochondrial kinase PINK1 contributes to signal amplification by antagonizing the M1-ubiquitin-specific deubiquitinase OTULIN.

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Wu, Z., Berlemann, L. A., Bader, V., Sehr, D. A., Eilers, E., Covallero, A., Meschede, J., Angersbach, L., Showkat, C., Michaelis, J. B., Muench, C., Rieger, B., Namgaladze, D., Herrera, M. G., Fiesel, F. C., Springer, W., Mendes, M., Stepien, J., Barkovits, K., Marcus, K., Sickmann, A., Dittmar, G., Busch, K. B., Riedel, D., Brini, M., Tatzelt, J., Cali, T., Winklhofer, K. F.. 2022-05-28. LUBAC assembles a signaling platform at mitochondria for signal amplification and shuttling of NF-ĸB to the nucleus. https://doi.org/10.1101/2022.05.27.493704

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