Key discoveries made by CIBSS Scientists:
- The discovery of a mechanistic link between the dynamic activity of multi-protein complexes involved in mitochondrial import and global cellular programs such as the cell division cycle (Science 2014). 12
- The discovery that epigenetics and metabolism are connected by a dual transcriptional regulator of nuclear and mitochondrial genomes (Cell 2016). 4
- Mechanistic insight into how T cell signalling and metabolic states are integrated with each other (Cell 2016 and Cell 2017). 2, 5
- The understanding of the nuclear signalling mechanisms that link zygotic gene activation to pluripotency control (Science 2013). 14
Here are some of the top publications of CIBSS Scientists (chronological list)
1. Membrane protein insertion through a mitochondrial β-barrel gate. Höhr AIC, Lindau C, Wirth C, Qiu J, Stroud DA, Kutik S, Guiard B, Hunte C, Becker T, Pfanner N*, Wiedemann N* (2018). Science 359, eaah6834. *corresponding
Elucidation of signal-mediated membrane protein insertion by the mitochondrial sorting and assembly machinery by position-specific crosslinking in the native membrane environment.
2. Mitochondrial priming by CD28. Klein Geltink RI, O’Sullivan D, Corrado M, Bremser A, Buck MD, Buescher JM, Firat E, Zhu X, Niedermann G, Caputa G, Kelly B, Warthorst U, Rensing-Ehl A, Kyle RL, Vandersarren L, Curtis JD, Patterson AE, Lawless S, Grzes K, Qiu J, Sanin DE, Kretz O, Huber TB, Janssens S, Lambrecht BN, Rambold AS, Pearce EJ, Pearce EL (2017). Cell 171, 385-397.
Demonstrates that signalling via the CD28 costimulatory receptor primes the mitochondria of T cells with latent metabolic capacity (by remodelling cristae and expanding spare respiratory capacity) that is crucial for the development of protective memory T cells.
Demonstrates that WOX2 (a transcription factor regulating early embryo patterning) has a crucial role in initiating the formation of shoot meristem stem cells by setting up the correct balance of the phytohormones in the primordium. This discovery links the regulation of early embryo cells and stem cells in plants.
4. MOF acetyl transferase regulates transcription and respiration in mitochondria. Chatterjee A, Seyfferth J, Lucci J, Gilsbach R, Preissl S, Böttinger L, Martensson CU, Panhale A, Stehle T, Kretz O, Sahyoun AH, Avilov S, Eimer S, Hein L, Pfanner N, Becker T, Akhtar A (2016). Cell 167, 722-738.
In a collaboration between CIBSS scientists, the first acetyl transferase with a dual function in regulation transcription in both the nuclear and mitochondrial genomes was discovered. This study paves the way to understand the crosstalk between epigenetic and metabolic control.
5. Mitochondrial dynamics controls T cell fate through metabolic reprogramming. Buck MD, O’Sullivan D, Klein Geltink RI, Curtis JD, Chang CH, Sanin DE, Qiu J, Kretz O, Braas D, van der Windt GJW, Chen Q, Huang S, O’Neill CM, Edelson BT, Pearce EJ, Sesaki H, Huber TB, Rambold AS, Pearce EL (2016). Cell 166, 63-76.
This publication was the first to show that mitochondrial dynamics facilitates metabolic adaptations in immune cells, and that distinct changes in cristae drive metabolism.
6. K+ efflux-independent NLRP3 inflammasome activation by small molecules targeting mitochondria. Groß CJ, Mishra R, Schneider KS, Médard G, Wettmarshausen J, Dittlein DC, Shi H, Gorka O, Koenig PA, Fromm S, Magnani G, Cikovic T, Hartjes L, Smollich J, Robertson AAB, Cooper MA, Schmidt-Supprian M, Schuster M, Schroder K, Broz P, Traidl-Hoffmann C, Beutler B, Kuster B, Ruland J, Schneider S, Perocchi F, Groß O (2016). Immunity 45, 761-773.
This publication demonstrates that the anti-cancer immunomodulatory imiquimod is a novel inhibitor or mitochondrial complex I, and that it induces NLRP3 activation by a ROS-dependent and (surprisingly) K+ efflux-independent mechanism.
7. A cholesterol-based allostery model of T cell receptor phosphorylation. Swamy M, Beck-Garcia K, Beck-Garcia E, Hartl FA, Morath A, Yousefi OS, Dopfer EP, Molnar E, Schulze AK, Blanco R, Borroto A, Martin-Blanco N, Alarcon B, Hofer T, Minguet S, Schamel WW (2016). Immunity 44,1091-1101.
This publication shows that T cell antigen receptors (pre-assembled nanoclusters and non-nanoclustered individual TCRs) are kept silent in the absence of ligand/antigen by cholesterol binding, whose concentration is regulated by the metabolic switch of the T cells.
8. Cellular delivery and photochemical release of a caged inositol-pyrophosphate induces PH-domain translocation in cellulo. Pavlovic I, Thakor DT, Vargas JR, McKinlay CJ, Hauke S, Anstaett P, Camuna RC, Bigler L, Gasser G, Schultz C, Wender PA*, Jessen HJ (2016). Nat. Commun. 7, 10622. *corresponding
This publication demonstrates that highly charged and photo-caged inositol pyrophosphates can be delivered into mammalian cells using polycationic transporter molecules. Upon uncaging, we were able to control the localisation of AKT in living cells.
The X-ray structure of proton-pumping and ROS producing mitochondrial respiratory complex I described in detail the canonical subunits that execute the bioenergetic function. It provided mechanistic clues for the coupling of redox-chemistry and proton pumping as well as for the active/deactive transition of the complex, a regulatory mechanism that controls ROS generation.
10. Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. 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). Nature 524, 485-488. *corresponding
Discovery of a new mechanism that protects cells containing dysfunctional mitochondria against the accumulation of mitochondrial precursor proteins in the cytosol via two arms: activation of the proteasome and inhibition of global protein translation.
11. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJW, Tonc E, Schreiber RD, Pearce EJ, Pearce EL (2015). Cell 162, 1229-1241.
This paper shows that glucose competition, as a distinct mechanism, can mediate tumour progression, even in highly antigenic tumours that are recognised by the immune system.
12. Cell cycle-dependent regulation of mitochondrial preprotein translocase. Harbauer AB, Opalińska M, Gerbeth C, Herman JS, Rao S, Schönfisch B, Guiard B, Schmidt O, Pfanner N*, Meisinger C* (2014). Science 346, 1109-1113. *corresponding
Discovery that the preprotein translocase of the mitochondrial outer membrane is regulated by cyclin-dependent kinase, revealing a cell cycle-specific control of mitochondrial biogenesis and respiratory activity.
13. Post-transcriptional control of T cell effector function by aerobic glycolysis. Chang CH, Curtis JD, Maggi Jr. LB, Faubert B, Villarino AV, O’Sullivan D, Huang SC, van der Windt GJW, Blagih J, Qiu J, Weber JD, Pearce EJ, Jones RG, Pearce EL (2013). Cell 153, 1239-1251.
This study demonstrated that the hallmark switch to aerobic glycolysis that T cells undergo during activation is a metabolically regulated signalling mechanism that specifically supports effector function. This regulation is mediated by post-transcriptional control of effector cytokine production by the glycolytic enzyme GAPDH.
SoxB1/Sox2 and Pou5f3/Oct4 transcription factors are shown to act as pioneer transcription factors before midblastula transition and prime zygotic gene activation. They reprogramme the zygote chromatin state to pluripotent blastomeres and prime expression of developmental genes for all embryonic lineages. This work reveals the evolutionary origin of pluripotency control to be zygotic gene activation.
15. Microglia emerge from erythromyeloid precursors via Pu.1- and IRF-8 dependent pathways. Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, Wieghofer P, Heinrich A, Riemke P, Hölscher C, Müller DN, Luckow B, Brocker T, Debowski K, Fritz G, Opdenakker G, Diefenbach A, Biber K, Heikenwalder M, Geissmann F, Rosenbauer F, Prinz M (2013). Nat. Neurosci. 16, 273-280.
Elucidation of the origin and differentiation programme of microglia (the resident tissue macrophages of the CNS) during embryonic development. Microglia derive from extraembryonic erythromyeloid progenitors in the yolk sac, colonise the CNS early during embryogenesis, and differentiate via a Pu.1- and Irf8-dependent pathway.
16. Vertebrate kidney tubules elongate using a planar cell polarity-dependent, rosette-based mechanism of convergent extension. Lienkamp SS, Liu K, Karner CM, Carroll TJ, Ronneberger O, Wallingford JB*, Walz G* (2012). Nat. Genet. 44, 1382-1387. *corresponding
This study, for the first time, visualised cell intercalation during vertebrate kidney development, and established rosette formation as a highly conserved cellular engine for epithelial morphogenesis.
17. Drosophila dosage compensation involves enhanced Pol II recruitment to male X-linked promoters. Conrad T, Cavalli FM, Vaquerizas JM, Luscombe NM*, Akhtar A* (2012). Science 337, 742-746. *corresponding
This study was important as CIBSS researchers showed for the first time that transcriptional regulation at the promoter is important for X chromosomal genes during the process of dosage compensation in flies. This study paves the way to understand the underlying mechanism of transcription control of X-linked genes.
18. ViBE-Z: a framework for 3D virtual colocalization analysis in zebrafish larval brains. Ronneberger O*, Liu K, Rath M, Rueß D, Mueller T, Skibbe H, Drayer B, Schmidt T, Filippi A, Nitschke R, Brox T, Burkhardt H, Driever W* (2012). Nat. Methods 9, 735-742. *corresponding
ViBE-Z established a software framework for integration of multiple gene expression data into an anatomical model of the zebrafish larval brain at single cell resolution. This platform will be instrumental to map gene expression data and signalling pathway reporter activity into 3D anatomical contexts such as neural stem cell niches and to develop integrated signalling models.
19. Development of a peptide that selectively activates protein phosphatase-1 in living cells. Chatterjee J, Beullens M, Sukackaite R, Qian J, Lesage B, Hart DJ, Bollen M*, Köhn M* (2012). Angew. Chem. Int. Ed. 51, 10054-10059. *corresponding
Chemical biology design of cell-penetrating peptides that selectively activate a phosphatase in living cells.
20. Photoconversion and nuclear trafficking cycles determine phytochrome A's response profile to far-red light. Rausenberger J, Tscheuschler A, Nordmeier W, Wüst F, Timmer J, Schäfer E, Fleck C*, Hiltbrunner A* (2011). Cell 146, 813-825. *corresponding
The paper shows how mathematical modelling is able to elucidate the 40 years old mystery that phytochrome A has the peak of its absorption spectrum in red light but the maximum of its action spectrum in far red light.
21. Regulation of mitochondrial protein import by cytosolic kinases. Schmidt O, Harbauer AB, Rao S, Eyrich B, Zahedi RP, Stojanovski D, Schonfisch B, Guiard B, Sickmann A, Pfanner N*, Meisinger C* (2011). Cell 144, 227-239. *corresponding
Discovery that the main protein entry gate of mitochondria is not a static complex, but is extensively regulated by cytosolic kinases in dependence on the metabolic state of the cell.
The first X-ray structure analysis of the entire mitochondrial respiratory complex I, obtained at low resolution, brought insight in the modular architecture of the proton-pumping and ROS producing complex and supported a mechanism by conformational coupling.
23. Native GABAB receptors are heteromultimers with a family of auxiliary subunits. Schwenk J, Metz M, Zolles G, Turecek R, Fritzius T, Bildl W, Tarusawa E, Kulik A, Unger A, Ivankova K, Seddik R, Tiao JY, Rajalu M, Trojanova J, Rohde V, Gassmann M, Schulte U, Fakler B*, Bettler B* (2010). Nature 465, 231-235. *corresponding
Using quantitative proteomic analysis this work identified a family of proteins, the KCTD-proteins, as novel auxiliary subunits for GABAB-receptors, the most abundant inhibitory G-protein coupled receptor in the mammalian brain. These novel subunits control the time-course of the receptor-mediated signalling.
First description of direct gene silencing by micro RNAs via DNA methylation. This epigenetic mechanism was discovered in moss and is now also discussed for human diseases like depression or cancer. Previously, only the translational inhibition of gene expression by micro RNAs was known.
25. Phosphorylation of histone H3T6 by PKCβI controls demethylation at histone H3K4. Metzger E, Imhof A, Patel D, Kahl P, Hoffmeyer K, Friedrichs N, Müller JM, Greschik H, Kirfel J, Ji S, Kunowska N, Beisenherz-Huss C, Günther T, Buettner R, Schüle R. (2010). Nature 464, 792-796.
This work established that androgen-dependent kinase signalling leads to the writing of the new chromatin mark H3T6ph, which in consequence prevents removal of active methyl marks from H3K4 during androgen receptor stimulated gene expression. This mechanism links androgen hormone signalling directly to chromatin regulation, and may potentially be important in prostate cancer.