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

Wu, Z., Berlemann, L. A., Bader, V., Sehr, D. A., Dawin, E., Covallero, A., et al. (2022). LUBAC assembles a ubiquitin signaling platform at mitochondria for signal amplification and transport of NF-κB to the nucleus. The EMBO Journal, 41(24): e112006. doi:10.15252/embj.2022112006.

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Item Permalink: https://hdl.handle.net/21.11116/0000-000C-45F3-4 Version Permalink: https://hdl.handle.net/21.11116/0000-000C-45F4-3
Genre: Journal Article
Other : LUBAC assembles a ubiquitin signaling platform at mitochondria for signal amplification and transport of NF-kappa B to the nucleus

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 Creators:
Wu, Zhixiao, Author
Berlemann, Lena A., Author
Bader, Verian, Author
Sehr, Dominik A., Author
Dawin, Eva, Author
Covallero, Alberto, Author
Meschede, Jens, Author
Angersbach, Lena, Author
Showkat, Cathrin, Author
Michaelis, Jonas B., Author
Muench, Christian, Author
Rieger, Bettina, Author
Namgaladze, Dmitry, Author
Herrera, Maria Georgina, Author
Fiesel, Fabienne C., Author
Springer, Wolfdieter, Author
Mendes, Marta, Author
Stepien, Jennifer, Author
Barkovits, Katalin, Author
Marcus, Katrin, Author
Sickmann, Albert, AuthorDittmar, Gunnar, AuthorBusch, Karin B., AuthorRiedel, Dietmar1, Author           Brini, Marisa, AuthorTatzelt, Joerg, AuthorCali, Tito, AuthorWinklhofer, Konstanze F., Author more..
Affiliations:
1Department of Structural Dynamics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350272              

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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-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.

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Language(s): eng - English
 Dates: 2022-11-182022-12-15
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.15252/embj.2022112006
 Degree: -

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Project name : We thank Jean-François Trempe for providing the tcPINK1 plasmid, Katrin Rittinger and Ben Stieglitz for the HOIP-RBR-LDD and UBE2L3 plasmids, Richard Youle for the p-S65-Parkin antibody, Daniel Krappmann for the OTULIN plasmids, Sadasivam Jeganathan for protein expression and purification, and Genentech for the 1F11/3F5/Y102L antibody. We also thank Günther Meschke for stimulating discussions. KFW is supported by the German Research Foundation (WI/2111-4, WI/2111-6, WI/2111/8, FOR 2848, and Germany's Excellence Strategy—EXC 2033-390677874—RESOLV) and the Michael J. Fox Foundation for Parkinson's Research (Grant IDs 16293 and 021968). SR-SIM microscopy was funded by the German Research Foundation and the State Government of North Rhine-Westphalia (INST 213/840-1 FUGG). TC is supported by grants from the Ministry of University and Research (Bando SIR 2014 no. RBSI14C65Z and PRIN2017) and from the Università degli Studi di Padova (Progetto Giovani 2012 no. GRIC128SP0 to T.C., Progetto di Ateneo 2016 no. CALI_- SID16_01, STARS Consolidator Grant 2019). M.B is supported by Local Funds from the University of Padova. CM is supported by the German Research Foundation (Project-ID 390339347, Emmy Noether Programme and Project-ID 259130777, CRC1177). WS is supported by the National Institutes of Health (NS085070, NS110085, and NS110435), the Department of Defense Congressionally Directed Medical Research Programs (W81XWH-17-1-0248), the Michael J. Fox Foundation for Parkinson's Research, Mayo Clinic Foundation and the Center for Biomedical Discovery (CBD).
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Title: The EMBO Journal
Source Genre: Journal
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Publ. Info: Nature Publishing Group
Pages: - Volume / Issue: 41 (24) Sequence Number: e112006 Start / End Page: - Identifier: ISSN: 0261-4189
CoNE: https://pure.mpg.de/cone/journals/resource/954925497061_1