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Author: Marcus, Katrin ×

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    The cytosolic domain of Pex22p stimulates the Pex4p-dependent ubiquitination of the PTS1-receptor
    (San Francisco, CA : Public Library of Science, 2014) El Magraoui, Fouzi; Schrötter, Andreas; Brinkmeier, Rebecca; Kunst, Lena; Mastalski, Thomas; Müller, Thorsten; Marcus, Katrin; Meyer, Helmut E.; Girzalsky, Wolfgang; Erdmann, Ralf; Platta, Harald W.
    Peroxisomal biogenesis is an ubiquitin-dependent process because the receptors required for the import of peroxisomal matrix proteins are controlled via their ubiquitination status. A key step is the monoubiquitination of the import receptor Pex5p by the ubiquitin-conjugating enzyme (E2) Pex4p. This monoubiquitination is supposed to take place after Pex5p has released the cargo into the peroxisomal matrix and primes Pex5p for the extraction from the membrane by the mechano-enzymes Pex1p/Pex6p. These two AAA-type ATPases export Pex5p back to the cytosol for further rounds of matrix protein import. Recently, it has been reported that the soluble Pex4p requires the interaction to its peroxisomal membrane-anchor Pex22p to display full activity. Here we demonstrate that the soluble C-terminal domain of Pex22p harbours its biological activity and that this activity is independent from its function as membrane-anchor of Pex4p. We show that Pex4p can be functionally fused to the trans-membrane segment of the membrane protein Pex3p, which is not directly involved in Pex5p-ubiquitination and matrix protein import. However, this Pex3(N)-Pex4p chimera can only complement the double-deletion strain pex4Δ/pex22Δ and ensure optimal Pex5p-ubiquitination when the C-terminal part of Pex22p is additionally expressed in the cell. Thus, while the membrane-bound portion Pex22(N)p is not required when Pex4p is fused to Pex3(N)p, the soluble Pex22(C)p is essential for peroxisomal biogenesis and efficient monoubiquitination of the import receptor Pex5p by the E3-ligase Pex12p in vivo and in vitro. The results merge into a picture of an ubiquitin-conjugating complex at the peroxisomal membrane consisting of three domains: the ubiquitin-conjugating domain (Pex4p), a membrane-anchor domain (Pex22(N)p) and an enhancing domain (Pex22(C)p), with the membrane-anchor domain being mutually exchangeable, while the Ubc- and enhancer-domains are essential.
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    LUBAC assembles a ubiquitin signaling platform at mitochondria for signal amplification and transport of NF-κB to the nucleus
    (Hoboken, NJ [u.a.] : Wiley, 2022) 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, Maria 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; Cali, Tito; Winklhofer, Konstanze F.
    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.