LUBAC assembles a ubiquitin signaling platform at mitochondria for signal amplification and transport of NF‐κB to the nucleus
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‐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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 18, 2022
- Source ID
- 10.15252/embj.2022112006
Entities
People
- Albert Sickmann
- Alberto Covallero
- Bettina Rieger
- Cathrin Showkat
- Christian Münch
- Dietmar Riedel
- Dmitry Namgaladze
- Dominik A Sehr
- Eva Dawin
- Fabienne C. Fiesel
- Gunnar Dittmar
- Jennifer Stepien
- Jens Meschede
- Jonas B. Michaelis
- Jorg Tatzelt
- Karin B Busch
- Katalin Barkovits
- Katrin Marcus
- Konstanze Winklhofer
- Lena A Berlemann
- Lena Angersbach
- Maria Georgina Herrera
- Marisa Brini
- Marta Mendes
- Tito Calì
- Verian Bader
- Wolfdieter Springer
- Zhixiao Wu
Organizations
- Congressionally Directed Medical Research Programs
- German Research Foundation
- Goethe University Frankfurt
- Luxembourg Institute of Health
- Mayo Clinic
- Mayo Clinic Graduate School of Biomedical Sciences
- Ministry of Education, Universities and Research
- National Institutes of Health
- Ruhr University Bochum
- The Michael J. Fox Foundation
- University of Münster
- University of Padua