Protein Quality Control
Mitochondria are essential for most cellular processes and a cell’s very own survival. To remain active and functional, mitochondria need to control the synthesis and folding of their proteins. However, many cellular perturbations, including major diseases like neurodegenerative diseases and cancer, can harm mitochondria’s protein folding homeostasis, with potentially fatal consequences for cells.
Figure: UPRmt halts mitochondrial translation. From Münch and Harper, Nature 2016. |
Research in the Münch laboratory focuses on the mitochondrial protein quality control responses in mammalian cells upon mitochondrial protein misfolding, particularly the mitochondrial unfolded protein response (UPRmt). During protein folding stress in mitochondria, UPRmt elicits a transcriptional response to induce genes such as chaperonins to increase the mitochondrial folding capacity. Additionally, as we recently showed, UPRmt also contains a translational response that reduces the folding load of proteins inside mitochondria by reversibly halting mitochondrial translation (Figure). We aim to further understand and define the processes involved in the UPRmt and other mitochondrial stress responses upon protein misfolding and to gain insight into the pathways that protect from mitochondrial and cellular damage. The lab heavily relies on our expertise in quantitative mass spectrometry in combination with cutting-edge cell biological, biochemical, gene editing, and next-generation sequencing approaches as tools to address our biological questions.
We are grateful to the funders of our work: European Research Council (ERC Starting Grant), German Research Foundation and the Emmy Noether Program, HMWK LOEWE Center for Cell and Gene Therapy, CRC 1177 on Selective Autophagy (SFB), Johanna Quandt Young Academy at Goethe, Frankfurt Cancer Institute, Mildred-Scheel-Nachwuchszentrums Frankfurt, and Else Kröner-Forschungskolleg Frankfurt.
Dr. Christian Münch
Christian Münch studied Biochemistry at the University of Tübingen and the Max Planck Institutes in Martinsried and Tübingen (Germany). He obtained his PhD from the University of Cambridge (UK), working on protein aggregation and prion-like processes in neurodegenerative diseases with Anne Bertolotti at the Laboratory of Molecular Biology. For his postdoctoral work, Christian joined Wade Harper’s laboratory at Harvard Medical School to study cellular protein quality control and the mitochondrial unfolded protein response.
Since 2016, Christian has been independent group leader and head of the Quantitative Proteomics Unit at the Institute of Biochemistry II (Goethe University Frankfurt, Germany). His main research interests focus on cellular stress responses to mitochondrial protein misfolding, infection and disease. Besides biochemical and molecular biology methods, his laboratory applies and develops proteomics methods to measure cellular dynamics after stress on a systems biology level. One major goal is to combine molecular with global information to gain a cell-wide understanding of cellular changes upon stress. For his work, Christian received an ERC Starting Grant, an Emmy Noether Grant and won a number of prizes, including the British Neuroscience Association Postgraduate Award, the Aventis Foundation Bridge Award and the Binder Innovation Prize of the German Society for Cell Biology.
Aneesha Kohli

Benedikt Sauer
Benedikt studied medicine at the Goethe University in Frankfurt am Main. He conducted his MD thesis work in the lab of Joachim Steinbach at the Dr. Senckenberg Institute of Neurooncology. In 2020, he started his medical residency in neurology at the University Hospital Frankfurt and, funded by the Patenschaftsmodell of the Frankfurt Research Funding, initiated a collaborative project with the Münch laboratory. In this project, he focuses on the mechanisms underlying metabolic adaption to the microenvironment in glioblastoma.
Dr. rer. nat Georg Tascher
Ines Gößner
Jasmin Schäfer
After completing an apprenticeship as biological lab technician, Jasmin studied Biochemistry at Goethe University in Frankfurt am Main. She found her passion for cellular stress responses during a three-month internship in Peter Walter’s lab at University of California, San Francisco. Jasmin obtained her PhD from Heidelberg University, where she joined the laboratory of Sebastian Schuck at the Center for Molecular Biology of Heidelberg University (ZMBH). During her thesis work, she investigated a stress-induced microautophagic pathway for selective degradation of endoplasmic reticulum and demonstrated the involvement of the ESCRT machinery. Jasmin joined the Münch lab in the beginning of 2020 as a postdoctoral researcher to study the mitochondrial unfolded protein response.
Jonas Michaelis
Kevin Klann
Martin Adrian-Allgood
In 2012, Martin graduated as Biological Technical Assistant (BTA) in Koblenz and started working in the Kerschensteiner laboratory at the Institute of Clinical Neuroimmunology in Munich focusing on protein production for the MS research. From 2016 till 2019, he was part of the research group Schmidt at the Institute for Microscopic Anatomy and Neurobiology in Mainz, gaining further experience in the production and purification of proteins for cancer research. In 2020, Martin joined the IBCII to support the Protein Quality Control Group of Christian Münch and the Quantitative Mass Spectrometry Unit.
Melinda Brunstein
Dr. Rebecca George Tharyan
Rebecca, hails from Kerala, India and obtained her Bachelor’s degree in B. tech Genetic Engineering from SRM University, Chennai, India. She moved to Germany and received her Master’s Degree from the University of Cologne. During her Master's, she got interested in the molecular genetics of stress responses and ageing research. She carried out her Ph. D under the supervision of Prof. Dr. Adam Antebi at the Max-Plank Institute for Biology of Ageing, Cologne, Germany. During her doctorate work, she focused on how mitochondrial function, stress response and intra-cellular crosstalk regulate longevity. She joined the Münch lab in Novbember 2020 to study the role of cellular stress responses during infection.
Dr. FX Reymond Sutandy
Sebastian Koschade
Sebastian studied medicine at the University of Regensburg (Germany). He conducted his MD thesis work in the lab of Prof. Dr. Ernst Tamm at the Department of Anatomy and Embryology. In 2016, he started his medical residency in internal medicine with a specialization in Hematology & Oncology at the University Hospital Frankfurt and joined the acute myeloid leukemia research group of Prof. Dr. Christian Brandts. With funding by the Mildred-Scheel-Nachwuchszentrum Frankfurt, he started a research project with the Münch lab in 2019, using quantitative proteomics to understand protein dynamics in acute myeloid leukemia.
Shady Amr
Süleyman Bozkurt
Süleyman completed his undergraduate in molecular biology and genetics at Izmir Institute of Technology in Turkey. During his Master's at Acıbadem Mehmet Ali Aydınlar University, he worked on CDP-choline's effects on mitophagy and mitochondrial dynamics. He also carried out work on TFEB in Katja Simon’s Lab at the University of Oxford. He joined the Münch lab in 2019 to study the effects of mitochondrial stress on mitochondrial proteostasis and mitophagy.
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Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy 2021. 1-382 Link
Klann K, Münch C. Biospektrum (Heidelb) 2021. 27 (1) 40-45 Link
Meyer N, Henkel L, Linder B, Zielke S, Tascher G, Trautmann S, Geisslinger G, Münch C, Fulda S, Tegeder I, Kögel D. Autophagy activation, lipotoxicity and lysosomal membrane permeabilization synergize to promote pimozide- and loperamide-induced glioma cell death. Autophagy 2021. 1-20 Link
Güllülü Ö, Hehlgans S, Mayer BE, Gößner I, Petraki C, Hoffmann M, Dombrowsky MJ, Kunzmann P, Hamacher K, Strebhardt K, Fokas E, Rödel C, Münch C, Rödel F. A spatial and functional interaction of a heterotetramer Survivin-DNA-PKcs complex in DNA damage response. Cancer Res 2021. Link
Hiebel C, Stürner E, Hoffmeister M, Tascher G, Schwarz M, Nagel H, Behrends C, Münch C, Behl C. BAG3 Proteomic Signature under Proteostasis Stress. Cells 2020. 9 (11) Link
Bojkova D, Bechtel M, McLaughlin KM, McGreig JE, Klann K, Bellinghausen C, Rohde G, Jonigk D, Braubach P, Ciesek S, Münch C, Wass MN, Michaelis M, Cinatl J. Aprotinin Inhibits SARS-CoV-2 Replication. Cells 2020. 9 (11) Link
Klann K, Münch C. Unbiased translation proteomics upon cell stress. Mol Cell Oncol 2020. 7 (4) 1763150 Link
Klann K, Bojkova D, Tascher G, Ciesek S, Münch C, Cinatl J. Growth Factor Receptor Signaling Inhibition Prevents SARS-CoV-2 Replication. Mol Cell 2020. 80 (1) 164-174.e4 Link
McLaughlin KM, Bechtel M, Bojkova D, Münch C, Ciesek S, Wass MN, Michaelis M, Cinatl J. COVID-19-Related Coagulopathy-Is Transferrin a Missing Link? Diagnostics (Basel) 2020. 10 (8) Link
Osthues T, Zimmer B, Rimola V, Klann K, Schilling K, Mathoor P, Angioni C, Weigert A, Geisslinger G, Münch C, Scholich K, Sisignano M. The Lipid Receptor G2A (GPR132) Mediates Macrophage Migration in Nerve Injury-Induced Neuropathic Pain. Cells 2020. 9 (7) Link
Klann K, Münch C. Instrument Logic Increases Identifications during Mutliplexed Translatome Measurements. Anal Chem 2020. 92 (12) 8041-8045 Link
Bojkova D, Klann K, Koch B, Widera M, Krause D, Ciesek S, Cinatl J, Münch C. Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature 2020. 583 (7816) 469-472 Link
Key J, Maletzko A, Kohli A, Gispert S, Torres-Odio S, Wittig I, Heidler J, Bárcena C, López-Otín C, Lei Y, West AP, Münch C, Auburger G. Loss of mitochondrial ClpP, Lonp1, and Tfam triggers transcriptional induction of Rnf213, a susceptibility factor for moyamoya disease. Neurogenetics 2020. 21 (3) 187-203 Link
Engel AL, Lorenz NI, Klann K, Münch C, Depner C, Steinbach JP, Ronellenfitsch MW, Luger AL. Serine-dependent redox homeostasis regulates glioblastoma cell survival. Br J Cancer 2020. 122 (9) 1391-1398 Link
Prieto-Garcia C, Hartmann O, Reissland M, Braun F, Fischer T, Walz S, Schülein-Völk C, Eilers U, Ade CP, Calzado MA, Orian A, Maric HM, Münch C, Rosenfeldt M, Eilers M, Diefenbacher ME. Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells. EMBO Mol Med 2020. 12 (4) e11101 Link
Klann K, Tascher G, Münch C. Functional Translatome Proteomics Reveal Converging and Dose-Dependent Regulation by mTORC1 and eIF2α. Mol Cell 2020. 77 (4) 913-925.e4 Link
Pitzius S, Osterburg C, Gebel J, Tascher G, Schäfer B, Zhou H, Münch C, Dötsch V. TA*p63 and GTAp63 achieve tighter transcriptional regulation in quality control by converting an inhibitory element into an additional transactivation domain. Cell Death Dis 2019. 10 (10) 686 Link
Key J, Mueller AK, Gispert S, Matschke L, Wittig I, Corti O, Münch C, Decher N, Auburger G. Ubiquitylome profiling of Parkin-null brain reveals dysregulation of calcium homeostasis factors ATP1A2, Hippocalcin and GNA11, reflected by altered firing of noradrenergic neurons. Neurobiol Dis 2019. 127 114-130 Link
Poluzzi C, Nastase MV, Zeng-Brouwers J, Roedig H, Hsieh LT, Michaelis JB, Buhl EM, Rezende F, Manavski Y, Bleich A, Boor P, Brandes RP, Pfeilschifter J, Stelzer EHK, Münch C, Dikic I, Brandts C, Iozzo RV, Wygrecka M, Schaefer L. Biglycan evokes autophagy in macrophages via a novel CD44/Toll-like receptor 4 signaling axis in ischemia/reperfusion injury. Kidney Int 2019. 95 (3) 540-562 Link
Nguyen TD, Shaid S, Vakhrusheva O, Koschade SE, Klann K, Thölken M, Baker F, Zhang J, Oellerich T, Sürün D, Derlet A, Haberbosch I, Eimer S, Osiewacz HD, Behrends C, Münch C, Dikic I, Brandts CH. Loss of the selective autophagy receptor p62 impairs murine myeloid leukemia progression and mitophagy. Blood 2019. 133 (2) 168-179 Link
Münch C. The different axes of the mammalian mitochondrial unfolded protein response. BMC Biol 2018. 16 (1) 81 Link
Meyer N, Zielke S, Michaelis JB, Linder B, Warnsmann V, Rakel S, Osiewacz HD, Fulda S, Mittelbronn M, Münch C, Behrends C, Kögel D. AT 101 induces early mitochondrial dysfunction and HMOX1 (heme oxygenase 1) to trigger mitophagic cell death in glioma cells. Autophagy 2018. 14 (10) 1693-1709 Link
Münch C, Dikic I. Publisher Correction: Hitchhiking on selective autophagy. Nat Cell Biol 2018. 20 (8) 990 Link
Münch C, Dikic I. Hitchhiking on selective autophagy. Nat Cell Biol 2018. 20 (2) 122-124 Link
Yamano K, Wang C, Sarraf SA, Münch C, Kikuchi R, Noda NN, Hizukuri Y, Kanemaki MT, Harper W, Tanaka K, Matsuda N, Youle RJ. Endosomal Rab cycles regulate Parkin-mediated mitophagy. Elife 2018. 7 Link
Drané P, Brault ME, Cui G, Meghani K, Chaubey S, Detappe A, Parnandi N, He Y, Zheng XF, Botuyan MV, Kalousi A, Yewdell WT, Münch C, Harper JW, Chaudhuri J, Soutoglou E, Mer G, Chowdhury D. TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature 2017. 543 (7644) 211-216 Link
Yang W, Nagasawa K, Münch C, Xu Y, Satterstrom K, Jeong S, Hayes SD, Jedrychowski MP, Vyas FS, Zaganjor E, Guarani V, Ringel AE, Gygi SP, Harper JW, Haigis MC. Mitochondrial Sirtuin Network Reveals Dynamic SIRT3-Dependent Deacetylation in Response to Membrane Depolarization. Cell 2016. 167 (4) 985-1000.e21 Link
Münch C, Harper JW. Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation. Nature 2016. 534 (7609) 710-3 Link
Ordureau A, Münch C, Harper JW. Quantifying ubiquitin signaling. Mol Cell 2015. 58 (4) 660-76 Link
Suraweera A, Münch C, Hanssum A, Bertolotti A. Failure of amino acid homeostasis causes cell death following proteasome inhibition. Mol Cell 2012. 48 (2) 242-53 Link
Münch C, Bertolotti A. Propagation of the prion phenomenon: beyond the seeding principle. J Mol Biol 2012. 421 (4-5) 491-8 Link
Münch C, Bertolotti A. Self-propagation and transmission of misfolded mutant SOD1: prion or prion-like phenomenon? Cell Cycle 2011. 10 (11) 1711 Link
Münch C, O'Brien J, Bertolotti A. Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc Natl Acad Sci U S A 2011. 108 (9) 3548-53 Link
Münch C, Bertolotti A. Exposure of hydrophobic surfaces initiates aggregation of diverse ALS-causing superoxide dismutase-1 mutants. J Mol Biol 2010. 399 (3) 512-25 Link
Mitochondrial homeostasis is crucial for cell viability. As in other cellular compartments, protein homeostasis (proteostasis) in mitochondria is maintained by a complex network controlling protein import/synthesis, folding, and degradation. Upon mitochondrial protein misfolding, the mitochondrial unfolded protein response (mtUPR) activates to (via so far unclear signaling pathways) induce a transcriptional response leading to an increase in the folding capacity, particularly via mitochondrial chaperonins (reviewed in Münch, BMC Biology, 2018). While the mtUPR is well studied and characterized in C. elegans, our understanding of the signaling and molecular mechanisms underlying the mtUPR in mammalian cells remains lacking.
Figure 1: Induction of the integrated stress response, mitochondrial UPR, and ER UPR by various cellular stresses. Treatments as indicated, induction of stress markers was determined by qPCR. Based on data from Münch and Harper, Nature 2016.
Adding to the complexity of studying the mammalian mtUPR, a wide range of mitochondrial stresses not causing protein misfolding lead to activation of the integrated stress response, but not mtUPR markers (Figure 1 and Münch and Harper, Nature, 2016). Chaperonin-induction remains specific to the response to protein unfolding. This observation shows a central role of the integrated stress response to respond to various mitochondrial stresses in addition to numerous cellular stresses. However, it also reveals that there appears to be a specific mtUPR signaling that relays information on mitochondrial proteostasis to a specific transcriptional output, including chaperonin induction.
Figure 2: Stress responses are acute. From Münch, BMC Biology 2018.
One major aspect in studying stress responses is their highly transient nature, typically lasting several hours with chronic activation leading to compensation and cell death (Figure 2, Münch, BMC Biology 2018). Thus, to investigate acute responses to unfolded mitochondrial proteins, we utilize chemical inhibitors that rapidly induce protein misfolding to allow a time-resolved study of the resulting signaling and cellular modulation. Using these tools, we recently defined the acute transcriptional mtUPR and discovered a novel mtUPR axis leading to a decrease in mitochondrial RNA processing and translation. This pathway provides with an additional approach to restore mitochondrial (and cellular) proteostasis (Figure 3, Münch and Harper, Nature 2016).
Figure 3: Model of the transcriptional and translational mtUPR axes. From Münch and Harper, Nature, 2016.
Expending on our findings and employing our descried models, we are now addressing 1) how protein misfolding is sensed inside mitochondria, 2) what mechanisms relay this information to the cytosole, 3) which cytosolic pathway lead to activation of the transcriptional mtUPR, and 4) whether there are factors modulating the mtUPR. Answering these questions will help in understanding signaling of the highly complex mtUPR and its role in proteostasis perturbation.
Mitochondrial protein misfolding activates the mitochondrial unfolded protein response (mtUPR) in an attempt to restore proteostasis. Two protective mtUPR axes regulate transcription and translation to increase folding capacity and decrease folding load, respectively (Münch and Harper, Nature, 2016). However, how do cells respond when the mtUPR cannot repair mitochondrial defects?
We study the role of mitophagy to overcome proteostasis defects that cannot be resolved. Mitophagy is a selective autophagy pathway that leads to the labelling of defective mitochondria with phospho-ubiquitin (largely driven by the kinase PINK1 and E3 ubiquitin ligase PARKIN), driving formation of autophagosomes around the damaged mitochondria to target these to lysosome for their degradation.
Using various biochemical and mitophagy flux assays, we study the transition from a protective mtUPR to a degradative mtUPR response (i.e. mitophagy, Figure 1). The driving questions are 1) how do cells determine which response to activate, 2) does the transcriptional mtUPR drive mitphagy induction, 3) what are the mechanisms that detect mitochondrial protein misfolding to induce mitophagy.
Figure 1: Different axes of the mitochondrial unfolded protein response. Transition from the protective mtUPR axes, modulating transcription and translation to maintain mitochondria, to the degradative mitophagy response. Adapted from Münch, BMC Biology, 2018.
We combine sophisticated mass spectrometry instrumentation (ThermoFisher Orbitrap Fusion Lumos and QExactive HF) with streamlined, multiplexed workflows by tandem mass tagging (TMT), to unravel novel biological questions. Besides whole cell proteomics, for which we reproducibly quantify between 8,000 and 10,000 proteins with minimized inter-sample variation, we apply post-translational modification analysis, such as global phosphorylation states or ubiquitinomes, and quantify organellar sub-proteomes. For studying protein-protein interactions, we largely employ immunoprecipitation or proximity labeling (Apex, TurboID) approaches, typically combined with TMT for relative quantification.
Protein dynamics
We are extensively employing and developing methods to combining metabolic protein labelling (SILAC) and TMT-based multiplexing to study protein dynamics, such as translation and degradation. One major focus lies on measuring protein translation. There, we wanted to set up an experimental system that uses pulse labeling with heavy isotope amino acid (i.e. pulse-SILAC), as cells cannot distinguish these from the light isotope amino acids and thus labeling does not perturb the experimental system (i.e. the cell). However, due to median cellular protein half-lives of about two days, only several % of the proteome are newly synthesized within a couple of hours. This low stoichiometry of newly synthesized (and isotope-marked proteins) largely prevents the possibility for their analysis by mass spectrometry (Figure 1, Klann et al, Molecular Cell, 2020). We developed a method called multiplexed enhanced Protein Dynamics (mePROD) mass spectrometry that uses one TMT channel to spike in a boost channel to specifically enhance the signal of interest (i.e. heavy labeled peptides) to enable their quantification (Figure 1). This method allows quantifying translation of thousands of individual proteins after labeling for as little as 15 minutes. At the same time, mePROD is economical and requires limited sample input (<150,000 cells). Using this method, we defined the translatome changes brought about by activation of the integrated stress response or mTORC1 inhibition. Strikingly, both pathways target translation of the same proteins, consitent with their role in cap-dependent translation (Klann et al., Molecular Cell, 2020).
Figure 1: Principle of multiplexed enhanced Protein Dynamics (mePROD) proteomics. Typical dynamic SILAC approaches lead to a low heavy-to-light stoichiometry of peptides, remaining below the detection limit. mePROD includes a boost channel that selectively increases the intensity of heavy peaks to pass the detection limit, followed by quantification using TMT reporter ions. From Klann et al, Molecular Cell, 2020.
Data integration
Employing established and new proteomics methods provide with extensive and global insight into various cellular conditions. We integrate our data on proteome changes (quantitative proteomics of the proteome, translatome, degradome, interactome) with genetic data (next generation sequencing data, such as RNA-seq and ribosome profiling), and biochemical assays to view biological mechanisms in a system-wide manner (e.g. Figure 2). This approach allows monitor cellular processes from various angles and to model underlying pathways.
Figure 2: Integration of various treatments modulating the translatome to define cross-correlations and underlying functional clusters.
Reference list of proteomics-based publications by the lab
Klann K, Tascher G, Münch C. Functional Translatome Proteomics Reveal Converging and Dose-Dependent Regulation by mTORC1 and eIF2α. Mol. Cell 2020.
Pitzius S, Osterburg C, Gebel J, Tascher G, Schäfer B, Zhou H, Münch C, Dötsch V. TA*p63 and GTAp63 achieve tighter transcriptional regulation in quality control by converting an inhibitory element into an additional transactivation domain. Cell Death Dis 2019. 10 (10): 686.
Key J, Mueller AK, Gispert S, Matschke L, Wittig I, Corti O, Münch C, Decher N, Auburger G. Ubiquitylome profiling of Parkin-null brain reveals dysregulation of calcium homeostasis factors ATP1A2, Hippocalcin and GNA11, reflected by altered firing of noradrenergic neurons. Neurobiol. Dis. 2019. 127 (): 114-130.
Nguyen TD, Shaid S, Vakhrusheva O, Koschade SE, Klann K, Thölken M, Baker F, Zhang J, Oellerich T, Sürün D, Derlet A, Haberbosch I, Eimer S, Osiewacz HD, Behrends C, Münch C, Dikic I, Brandts CH. Loss of the selective autophagy receptor p62 impairs murine myeloid leukemia progression and mitophagy. Blood 2019. 133 (2): 168-179.
Yamano K, Wang C, Sarraf SA, Münch C, Kikuchi R, Noda NN, Hizukuri Y, Kanemaki MT, Harper W, Tanaka K, Matsuda N, Youle RJ. Endosomal Rab cycles regulate Parkin-mediated mitophagy. Elife 2018. 7 (): .
Drané P, Brault ME, Cui G, Meghani K, Chaubey S, Detappe A, Parnandi N, He Y, Zheng XF, Botuyan MV, Kalousi A, Yewdell WT, Münch C, Harper JW, Chaudhuri J, Soutoglou E, Mer G, Chowdhury D. TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature 2017. 543 (7644): 211-216.
Yang W, Nagasawa K, Münch C, Xu Y, Satterstrom K, Jeong S, Hayes SD, Jedrychowski MP, Vyas FS, Zaganjor E, Guarani V, Ringel AE, Gygi SP, Harper JW, Haigis MC. Mitochondrial Sirtuin Network Reveals Dynamic SIRT3-Dependent Deacetylation in Response to Membrane Depolarization. Cell 2016. 167 (4): 985-1000.e21.
Münch C, Harper JW. Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation. Nature 2016. 534 (7609): 710-3.
Ordureau A, Münch C, Harper JW. Quantifying ubiquitin signaling. Mol. Cell 2015. 58 (4): 660-76.
Christian Münch

Email: ch.muench@em.uni-frankfurt.de
Fax: +49 (0) 69 6301 5577
Phone: +49 (0) 69 6301-3715
Christian Münch

Email: ch.muench@em.uni-frankfurt.de
Fax: +49 (0) 69 6301 5577
Phone: +49 (0) 69 6301-3715
Institute of Biochemistry II
University Hospital Frankfurt
Goethe University
Theodor-Stern-Kai 7 / Building 75
60590 Frankfurt am Main
Germany
All IBCII Members Contact Data
SARS-CoV-2 infected host cell proteomics reveal potential therapy targets
The new coronavirus – SARS-CoV-2 – has been quickly spreading around the globe since the beginning of 2020. The resulting disease COVID-19 has become a world-wide pandemic. We teamed up with Jindrich Cinatl at the Institute of Medical Virology (University Hospital Frankfurt) to study SARS-CoV-2 and identify new therapy options. We developed a novel cellular infection system with viral isolates from a COVID-19 patient, characterized by proteomics how the host cell changes over time after SARS-CoV-2 infection, and tested drugs targeting the identified pathways. We revealed a number of drugs that efficiently prevented virus replication in cells showing potential therapeutic strategies against COVID-19.
The proteomics data is available as raw files, TMT_scheme and from our interactive online tool
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SARS-CoV-2 infected host cell proteomics reveal potential therapy targets. (Top) Experimental design, cells were infected with SARS-CoV-2 and changes in the host cell proteome and viral proteins monitored over time. (Left) Increase in SARS-CoV-2 viral proteins over time. (Right) Changes in clusters of nucleic acid biosynthesis upon SARS-CoV-2 infection. |
Growth factor receptor signaling inhibition prevents SARS-CoV-2 replication
Signaling events underlying the host cell response to SARS-CoV-2 remains unclear and hinder the development of COVID-19 therapeutic approaches. Employing a human cell infection model for SARS-CoV-2, we analyzed the dynamic changes of protein modification on a system-wide scale. We performed deep phospho-proteome analysis with tandem mass tag (TMT) multiplexing to reveal signaling upon infection. This comprehensive examination generally characterized signaling upon infection and identified growth factor signaling as key feature. Best known for its role in cancer, growth factor signaling has already been extensively targeted by drugs, from which many are already clinically approved. Usage of five drugs inhibiting growth factor receptor signaling prevented SARS-CoV-2 replication in cells and decreased total viral load. Growth factor receptor signaling is a strong candidate for COVID-19 treatment.
Link to publication in Molecular Cell
Total proteome and phosphoproteome data are available as RAW files
And Excel as files: Phospho and Proteome
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Figure: Growth factor receptor signaling inhibition prevents SARS-CoV-2 replication. (Top) Drug-target-interaction network showing significantly induced signaling molecules and corresponding, approved drugs targeting these molecules. (Bottom) Scheme of effect of growth factor signaling axes on SARS-CoV-2 replication. Without interference the PI3K and MAPK signaling axes are activated and allow viral replication. Inhibition of either axis by small molecule drugs prevents viral proliferation. |
PROteostasis Group of European New InvEstigators (PROGENIE)
Proteostasis
Proteins underlie numerous processes ranging from synthesis, folding, modification, trafficking, to degradation. The correct interplay of these affects is require for proteins to carry out their proper functions in cells. The overall process to keep all these functions in balance is called protein homeostasis (proteostasis). The proteostasis field includes aspects such as chaperones, the ubiquitin-proteasome system, autophagy, and stress responses. In the last years, proteostasis has become of particular interest due its key role in ageing and pathologies ranging from neurodegeneration to cancer.
PROGENIE
A couple of years ago, it became apparent that there is a lack of opportunity for new group leaders to discuss general topics specific to this career stage and to have a forum to discuss their recent results with an opportunity to gain advice from experts from the different areas of proteostasis. The result was the formation of the PROGENIE network (PROteostasis Group of European New InvEstigators). The group came to life with our first meeting of 13 young investigators in November 2017. This first group was largely recruited from the protein folding community and since has been gradually growing in size and scientific focus, now covering a wider part of proteostasis.
Activities
Our main activity is a yearly PROGENIE meeting organized by and for PROGENIE members only. There, everybody has a chance to present their research and to gain feedback (ranging from experimental suggestions to publication strategies), exposure, and to develop collaborations. In additions, we address topics important for new investigators regarding the field, science structures, grant opportunities, and strategies and advise for topics involved in setting up and running a laboratory. Resulting from these discussions, PROGENIE members published guidelines for early-career group leaders (doi:10.15252/embr.201847163).
In addition, it became clear that there is a need for training opportunities for graduate students and postdocs in the ever-growing proteostasis field. As a result, we initiated a biannual ‘Autumn School on Proteostasis’ with leaders in the proteostasis field and PROGENIE members offering presentations on review-like overviews on different aspects of proteostasis, conference-type updates on current research, and career advice. The schools offers opportunity to attendees to present their research projects and to meet leaders in the field and get their advice and input. We ran the first school in November 2018 in Croatia, which was a great success with a good atmosphere to network and to learn about proteostasis and science in general. Nicely, it resulted in four attending postdocs to write a review about the school. The second proteostasis school will take place November 2021 in Israel, funded by EMBO/FEBS. In her memory, we named the series ‘Susan Lindquist School on Proteostasis’.
Become a member
We are looking for new investigators located in Europe with a visible track record in the proteostasis field and who are in the beginning of setting up their own laboratories. If you are interested in joining, please send an email to contact.progenie@gmail.com with a short paragraph about you and your research.
Current members
Claes Andréasson (Stockholm University, Sweden)
David Balchin (Francis Crick Institute, UK)
Ivana Bjedov (University College London, UK)
Marion Bouchecareilh (University of Bordeaux, CNRS, INSERM, France)
Piotr Bragoszewski (University of Warsaw, Poland)
Matthias Feige (Technical University of Munich, Germany)
Olivier Genest (Aix Marseille University, CNRS, France)
Paolo Grumati (Telethon Institute of Genetics and Medicine, Italy)
Elif Karagoez (Max Perutz Laboratories and Medical University of Vienna, Austria)
Anton Khmelinskii (Institute of Molecular Biology at Mainz, Germany)
Janine Kirstein (University of Bremen, Germany)
Anita Krisko (University Medical Center, Göttingen, Germany)
Christian Münch (Goethe University Frankfurt, Germany)
Natalia Rodríguez-Muela (DZNE-Dresden, Germany)
Rina Rosenzweig (Weizmann Institute of Science, Israel)
Adrien Rousseau (MRC-PPU, UK)
Juha Saarikangas (University of Helsinki, Finland)
Rahul Samant (Babraham Institute, Cambridge, UK)
Ritwick Sawarkar (MRC and University of Cambridge, UK)
Ruth Scherz-Shouval (Weizmann Institute of Science, Israel)
Reut Shalgi (Technion, Israel)
Ayala Shiber (Technio, Israel)
Rebecca Taylor (MRC-LMB, UK)
Patricija Van Oosten-Hawle (University of Leeds, UK)