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

Wu, Zhixiao; Berlemann, Lena A.; Bader, Verian; Sehr, Dominik A.; Dawin, Eva; Covallero, Alberto; Meschede, Jens; Angersbach, Lena; Showkat, Cathrin; Michaelis, Jonas B.; Münch, Christian; Rieger, Bettina; Namgaladze, Dmitry; Herrera, María Georgina; Fiesel, Fabienne C.; Springer, Wolfdieter; Mendes, Marta; Stepien, Jennifer; Barkovits, Katalin; Marcus, Katrin; Sickmann, Albert; Dittmar, Gunnar; Busch, Karin B.; Riedel, Dietmar; Brini, Marisa; Tatzelt, Jörg; Calì, Tito; Winklhofer, Konstanze F.

doi:10.15252/embj.2022112006

Cited by 17 publications

(12 citation statements)

References 122 publications

(164 reference statements)

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“…Because the abundance of M1-linked ubiquitin chains under basal conditions is extremely low, a stimulus-induced increase of M1-ubiquitin chain formation is perfectly suited to induce this transition. We recently discovered that M1- and K63-linked ubiquitin chains are formed at the mitochondrial outer membrane in response to TNF and IL-1β stimulation, resulting in IKK complex activation ( Wu et al, 2022 ). Thus, mitochondria may provide a membrane scaffold for NEMO condensate formation that allows efficient signal amplification based on the large surface of mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Linear ubiquitination induces NEMO phase separation to activate NF-κB signaling

et al. 2023

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The NF-κB essential modulator NEMO is the core regulatory component of the inhibitor of κB kinase complex, which is a critical checkpoint in canonical NF-κB signaling downstream of innate and adaptive immune receptors. In response to various stimuli, such as TNF or IL-1β, NEMO binds to linear or M1-linked ubiquitin chains generated by LUBAC, promoting its oligomerization and subsequent activation of the associated kinases. Here we show that M1-ubiquitin chains induce phase separation of NEMO and the formation of NEMO assemblies in cells after exposure to IL-1β. Phase separation is promoted by both binding of NEMO to linear ubiquitin chains and covalent linkage of M1-ubiquitin to NEMO and is essential but not sufficient for its phase separation. Supporting the functional relevance of NEMO phase separation in signaling, a pathogenic NEMO mutant, which is impaired in both binding and linkage to linear ubiquitin chains, does not undergo phase separation and is defective in mediating IL-1β–induced NF-κB activation.

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Section: Discussionmentioning

confidence: 99%

Linear ubiquitination induces NEMO phase separation to activate NF-κB signaling

et al. 2023

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“…The suppression of the tryptophan-melatonin pathway, therefore, has an array of consequences for mitochondrial function, including ROS production and ROS-driven microRNAs (miRNAs) that can then shape patterned gene induction. This may have relevance to recent data showing tumor necrosis factor (TNF)α to remodel the outer mitochondrial membrane via the induction of the linear ubiquitin chain assembly complex (LUBAC), with this change in the mitochondrial outer membrane facilitating the transport of activated NF-κB to the nucleus [121]. Whether a melatonin film over the mitochondrial membrane from loosely binding to hundreds of different receptors occludes the capacity of LUBAC to remodel the mitochondrial membrane and enhance NF-kB-driven inflammatory transcriptions will be important to determine.…”

Section: Gut Microbiome Melatonergic Pathway and Mitochondriamentioning

confidence: 60%

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

Anderson¹,

Almulla

Reíter

et al. 2023

Cells

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Although previously restricted to a limited number of medical conditions, there is a growing appreciation that ‘autoimmune’ (or immune-mediated) processes are important aspects of a wide array of diverse medical conditions, including cancers, neurodegenerative diseases and psychiatric disorders. All of these classes of medical conditions are associated with alterations in mitochondrial function across an array of diverse cell types. Accumulating data indicate the presence of the mitochondrial melatonergic pathway in possibly all body cells, with important consequences for pathways crucial in driving CD8+ T cell and B-cell ‘autoimmune’-linked processes. Melatonin suppression coupled with the upregulation of oxidative stress suppress PTEN-induced kinase 1 (PINK1)/parkin-driven mitophagy, raising the levels of the major histocompatibility complex (MHC)-1, which underpins the chemoattraction of CD8+ T cells and the activation of antibody-producing B-cells. Many factors and processes closely associated with autoimmunity, including gut microbiome/permeability, circadian rhythms, aging, the aryl hydrocarbon receptor, brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) all interact with the mitochondrial melatonergic pathway. A number of future research directions and novel treatment implications are indicated for this wide collection of poorly conceptualized and treated medical presentations. It is proposed that the etiology of many ‘autoimmune’/‘immune-mediated’ disorders should be conceptualized as significantly determined by mitochondrial dysregulation, with alterations in the mitochondrial melatonergic pathway being an important aspect of these pathoetiologies.

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“…Instead, for the contacts represented in the blue star cartoon, no specific proximity-driven fluorescent tools are yet available. Mitochondria-nucleus SPLICS is described in Wu et al, 2022. the level of colocalization between the fluorescent signals from the two involved organelles. This parameter is quantified as the level of pixel-pixel overlap or correlation with Pearson's and Mander's coefficients (Dunn et al, 2011).…”

Section: Microscopy-related Techniquesmentioning

confidence: 99%

Get Closer to the World of Contact Sites: A Beginner's Guide to Proximity-Driven Fluorescent Probes

Poggio

Brini

Calì

2022

Contact

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To maintain cellular homeostasis and to coordinate the proper response to a specific stimulus, information must be integrated throughout the cell in a well-organized network, in which organelles are the crucial nodes and membrane contact sites are the main edges. Membrane contact sites are the cellular subdomains where two or more organelles come into close apposition and interact with each other. Even though many inter-organelle contacts have been identified, most of them are still not fully characterized, therefore their study is an appealing and expanding field of research. Thanks to significant technological progress, many tools are now available or are in rapid development, making it difficult to choose which one is the most suitable for answering a specific biological question. Here we distinguish two different experimental approaches for studying inter-organelle contact sites. The first one aims to morphologically characterize the sites of membrane contact and to identify the molecular players involved, relying mainly on the application of biochemical and electron microscopy (EM)-related methods. The second approach aims to understand the functional importance of a specific contact, focusing on spatio-temporal details. For this purpose, proximity-driven fluorescent probes are the experimental tools of choice, since they allow the monitoring and quantification of membrane contact sites and their dynamics in living cells under different cellular conditions or upon different stimuli. In this review, we focus on these tools with the purpose of highlighting their great versatility and how they can be applied in the study of membrane contacts. We will extensively describe all the different types of proximity-driven fluorescent tools, discussing their benefits and drawbacks, ultimately providing some suggestions to choose and apply the appropriate methods on a case-to-case basis and to obtain the best experimental outcomes.

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

Cited by 17 publications

References 122 publications

Linear ubiquitination induces NEMO phase separation to activate NF-κB signaling

Linear ubiquitination induces NEMO phase separation to activate NF-κB signaling

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

Get Closer to the World of Contact Sites: A Beginner's Guide to Proximity-Driven Fluorescent Probes

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