Project 06:
Regulation of the human proteostasis network under mitochondrial protein import stress
Sven Dennerlein
E-Mail: sven.dennerlein@med.uni-goettingen.de
Phone: +49 551-39-65951
Department of Cellular Biochemistry
University Medical Center Göttingen
Silke Meiners
E-Mail: smeiners@fz-borstel.de
Phone: +49 4537-188-5846
Research Center Borstel - Leibniz Lung Center (FZB) and Christian-Albrechts University Kiel
Bettina Warscheid
E-Mail: bettina.warscheid@uni-wuerzburg.de
Phone: +49 931-31-84531/-86772
Biochemisty II, Theodor-Boveri-Institute and Biocenter University of Würzburg
Abstract
Mitochondrial functions depend on the import of nucleus-encoded mitochondrial proteins synthesized at cytosolic ribosomes. Thus, cytosolic protein synthesis is inevitably linked to mitochondrial protein import, and these processes are closely monitored by the cellular proteostasis network. However, how protein synthesis and proteasomal degradation are specifically regulated during acute mitochondrial import failures in human cells is still poorly understood. In this project, we will dissect regulatory processes for maintaining proteostasis during mitochondrial import stress using biochemical, proteomics and functional approaches.
Project-relevant publications
Poerschke S, Oeljeklaus S, Cruz-Zaragoza LD, Schenzielorz A, Dahal D, Hillen HS, Das H, Kremer LS, Valpadashi A, Breuer M, Sattmann J, Richter-Dennerlein R, Warscheid B, Dennerlein S, Rehling P (2024) Identification of TMEM126A as OXA1L-interacting protein reveals cotranslational quality control in mitochondria. Mol Cell. 84(2):345-358.e5.
Gerber M, Suppanz I, Oeljeklaus S, Niemann M, Käser S, Warscheid B, Schneider A, Dewar CE (2023) A Msp1-containing complex removes orphaned proteins in the mitochondrial outer membrane of T. brucei. Life Sci Alliance. 6(11):e202302004.
Javitt A, Shmueli MD, Kramer MP, Kolodziejczyk AA, Cohen IJ, Radomir L, Sheban D, Kamer I, Litchfield K, Bab-Dinitz E, Zadok O, Neiens V, Ulman A, Wolf-Levy H, Eisenberg-Lerner A, Kacen A, Alon M, Rêgo AT, Stacher-Priehse E, Lindner M, Koch I, Bar J, Swanton C, Samuels Y, Levin Y, da Fonseca PCA, Elinav E, Friedman N, Meiners S, Merbl Y (2023) The proteasome regulator PSME4 modulates proteasome activity and antigen diversity to abrogate antitumor immunity in NSCLC. Nat Cancer. 4(5):629-647.
Kim M, Serwa RA, Samluk L, Suppanz I, Kodroń A, Stępkowski TM, Elancheliyan P, Tsegaye B, Oeljeklaus S, Wasilewski M, Warscheid B, Chacinska A (2023) Immunoproteasome-specific subunit PSMB9 induction is required to regulate cellular proteostasis upon mitochondrial dysfunction. Nat Commun. 14(1):4092.
Wang X, Zhang H, Wang Y, Bramasole L, Guo K, Mourtada F, Meul T, Hu Q, Viteri V, Kammerl I, Konigshoff M, Lehmann M, Magg T, Hauck F, Fernandez IE, Meiners S (2023) DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T-cell immunity. EMBO J. 42(8):e110597.
Dewar CE, Oeljeklaus S, Mani J, Mühlhäuser WWD, von Känel C, Zimmermann J, Ochsenreiter T, Warscheid B, Schneider A (2022) Mistargeting of aggregation prone mitochondrial proteins activates a nucleus-mediated posttranscriptional quality control pathway in trypanosomes. Nat Commun. 13(1):3084.
Dennerlein S, Poerschke S, Oeljeklaus S, Wang C, Richter-Dennerlein R, Sattmann J, Bauermeister D, Hanitsch E, Stoldt S, Langer T, Jakobs S, Warscheid B, Rehling P (2021) Defining the interactome of the human mitochondrial ribosome identifies SMIM4 and TMEM223 as respiratory chain assembly factors. Elife. 10:e68213.
Morgenstern M, Peikert CD, Lübbert P, Suppanz I, Klemm C, Alka O, Steiert C, Naumenko N, Schendzielorz A, Melchionda L, Mühlhäuser WWD, Knapp B, Busch JD, Stiller SB, Dannenmaier S, Lindau C, Licheva M, Eickhorst C, Galbusera R, Zerbes RM, Ryan MT, Kraft C, Kozjak-Pavlovic V, Drepper F, Dennerlein S, Oeljeklaus S, Pfanner N, Wiedemann N, Warscheid B (2021) Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell Metab. 33(12):2464-2483.e18.
Meul T, Berschneider K, Schmitt S, Mayr CH, Mattner LF, Schiller HB, Yazgili AS, Wang X, Lukas C, Schlesser C, Prehn C, Adamski J, Graf E, Schwarzmayr T, Perocchi F, Kukat A, Trifunovic A, Kremer L, Prokisch H, Popper B, von Toerne C, Hauck SM, Zischka H, Meiners S (2020) Mitochondrial Regulation of the 26S Proteasome. Cell Rep. 32(8):108059.
Mårtensson CU, Priesnitz C, Song J, Ellenrieder L, Doan KN, Boos F, Floerchinger A, Zufall N, Oeljeklaus S, Warscheid B, Becker T (2019) Mitochondrial protein translocation-associated degradation. Nature. 569(7758):679-683.
Topf U, Suppanz I, Samluk L, Wrobel L, Böser A, Sakowska P, Knapp B, Pietrzyk MK, Chacinska A, Warscheid B (2018) Quantitative proteomics identifies redox switches for global translation modulation by mitochondrially produced reactive oxygen species. Nat Commun. 9(1):324.
Morgenstern M, Stiller SB, Lübbert P, Peikert CD, Dannenmaier S, Drepper F, Weill U, Höß P, Feuerstein R, Gebert M, Bohnert M, van der Laan M, Schuldiner M, Schütze C, Oeljeklaus S, Pfanner N, Wiedemann N, Warscheid B (2017) Definition of a high-confidence mitochondrial proteome at quantitative scale. Cell Rep. 19(13):2836-2852.
Peikert CD, Mani J, Morgenstern M, Käser S, Knapp B, Wenger C, Harsman A, Oeljeklaus S, Schneider A, Warscheid B (2017) Charting organellar importomes by quantitative mass spectrometry. Nat Commun. 8:15272.
Richter-Dennerlein R, Oeljeklaus S, Lorenzi I, Ronsör C, Bareth B, Schendzielorz AB, Wang C, Warscheid B, Rehling P, Dennerlein S (2016) Mitochondrial protein synthesis adapts to influx of nuclear-encoded protein. Cell. 167(2):471-483.e10.
Wrobel L, Topf U, Bragoszewski P, Wiese S, Sztolsztener ME, Oeljeklaus S, Varabyova A, Lirski M, Chroscicki P, Mroczek S, Januszewicz E, Dziembowski A, Koblowska M, Warscheid B, Chacinska A (2015) Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature. 524(7566):485-8.
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