LUBAC assembles a ubiquitin signaling platform at mitochondria for signal amplification and transport of NF‐κB to the nucleus

作者：Zhixiao Wu, Lena A. Berlemann, Verian Bader, Dominik A. Sehr, Eva Dawin, Alberto Covallero, Jens Meschede, Lena Angersbach, Cathrin Showkat, Jonas B. Michaelis, Christian Münch, Bettina Rieger, Dmitry Namgaladze, María Georgina Herrera, Fabienne C. Fiesel, Wolfdieter Springer, Marta L. Mendes, Jennifer Stepien, Katalin Barkovits, Katrin Marcus, Albert Sickmann, Gunnar Dittmar, Karin B. Busch, Dietmar Riedel, Marisa Brini, Jörg Tatzelt, Tito Calí, Konstanze F. Winklhofer · 发表于：The EMBO Journal · 年份：2022 · DOI：10.15252/embj.2022112006 · 被引用次数：39 · 研究领域：Ubiquitin and proteasome pathways、interferon and immune responses、Mitochondrial Function and Pathology

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‐κB pathway activated by TNF employs mitochondria as a platform for signal amplification and shuttling of activated NF‐κB to the nucleus. TNF treatment 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‐κB is locally activated and transported to the nucleus by mitochondria, leading to an increase in mitochondria‐nucleus contact sites in a HOIP‐dependent manner. Notably, TNF‐induced stabilization of the mitochondrial kinase PINK1 furthermore contributes to signal amplification by antagonizing the M1‐ubiquitin‐specific deubiquitinase OTULIN. Overall, our study reveals a role for mitochondria in amplifying TNF‐mediated NF‐κB activation, both serving as a signaling platform, as well as a transport mode for activated NF‐κB to the nuclear. The E3 ubiquitin ligase HOIP is the catalytic component the linear ubiquitin chain assembly complex (LUBAC) that regulates canonical NF‐κB activation in innate immune signaling. This study reports a role of mitoc...