Congratulations on your PhD!
Stefan Bauernfried
Humanes NLRP1 ist ein Sensor für Doppelstrang-RNA
RG: Veit Hornung
News
Stefan Bauernfried
Karl, L.A., Peritore, M., Galanti, L., and Pfander, B.
(IMPRS-LS students are in bold)
Front Genet, 2021, 12, 821543.
DOI: 10.3389/fgene.2021.821543
DNA Double Strand Break Repair and Its Control by Nucleosome Remodeling
DNA double strand breaks (DSBs) are repaired in eukaryotes by one of several cellular mechanisms. The decision-making process controlling DSB repair takes place at the step of DNA end resection, the nucleolytic processing of DNA ends, which generates single-stranded DNA overhangs. Dependent on the length of the overhang, a corresponding DSB repair mechanism is engaged. Interestingly, nucleosomes-the fundamental unit of chromatin-influence the activity of resection nucleases and nucleosome remodelers have emerged as key regulators of DSB repair. Nucleosome remodelers share a common enzymatic mechanism, but for global genome organization specific remodelers have been shown to exert distinct activities. Specifically, different remodelers have been found to slide and evict, position or edit nucleosomes. It is an open question whether the same remodelers exert the same function also in the context of DSBs. Here, we will review recent advances in our understanding of nucleosome remodelers at DSBs: to what extent nucleosome sliding, eviction, positioning and editing can be observed at DSBs and how these activities affect the DSB repair decision.
Oz, T., Mengoli, V., Rojas, J., Jonak, K., Braun, M., Zagoriy, I., and Zachariae, W.
(IMPRS-LS students/alumni are bold)
EMBO J, 2022, e109446.
DOI: 10.15252/embj.2021109446
The Spo13/Meikin pathway confines the onset of gamete differentiation to meiosis II in yeast
Sexual reproduction requires genome haploidization by the two divisions of meiosis and a differentiation program to generate gametes. Here, we have investigated how sporulation, the yeast equivalent of gamete differentiation, is coordinated with progression through meiosis. Spore differentiation is initiated at metaphase II when a membrane-nucleating structure, called the meiotic plaque, is assembled at the centrosome. While all components of this structure accumulate already at entry into meiosis I, they cannot assemble because centrosomes are occupied by Spc72, the receptor of the γ-tubulin complex. Spc72 is removed from centrosomes by a pathway that depends on the polo-like kinase Cdc5 and the meiosis-specific kinase Ime2, which is unleashed by the degradation of Spo13/Meikin upon activation of the anaphase-promoting complex at anaphase I. Meiotic plaques are finally assembled upon reactivation of Cdk1 at entry into metaphase II. This unblocking-activation mechanism ensures that only single-copy genomes are packaged into spores and might serve as a paradigm for the regulation of other meiosis II-specific processes.
Congratulations on your PhD!
Isa-Maria Gross
Combined Behavioral and Neural Investigations of Pup Retrieval - A neural code for pup call representations in the mouse auditory cortex
RG: Tobias Bonhoeffer
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Michael Bartoschek
Deciphering context-dependent amber suppression efficiency in mammalian cells with an expanded genetic code
RG: Heinrich Leonhardt
Reifschneider, A., Robinson, S., van Lengerich, B., Gnörich, J., Logan, T., Heindl, S., Vogt, M.A., Weidinger, E., Riedl, L., Wind, K., Zatcepin, A., Pesämaa, I., Haberl, S., Nuscher, B., Kleinberger, G., Klimmt, J., Götzl, J.K., Liesz, A., Bürger, K., Brendel, M., Levin, J., Diehl-Schmid, J., Suh, J., Di Paolo, G., Lewcock, J.W., Monroe, K.M., Paquet, D., Capell, A., and Haass, C.
(IMPRS-LS students are in bold)
EMBO J, 2022, e109108, online ahead of print.
DOI: 10.15252/embj.2021109108
Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency
Haploinsufficiency of the progranulin (PGRN)-encoding gene (GRN) causes frontotemporal lobar degeneration (GRN-FTLD) and results in microglial hyperactivation, TREM2 activation, lysosomal dysfunction, and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology, we used genetic and pharmacological approaches to suppress TREM2-dependent transition of microglia from a homeostatic to a disease-associated state. Trem2 deficiency in Grn KO mice reduced microglia hyperactivation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies led to reduced TREM2 signaling due to its enhanced shedding. Furthermore, TREM2 antibody-treated PGRN-deficient microglia derived from human-induced pluripotent stem cells showed reduced microglial hyperactivation, TREM2 signaling, and phagocytic activity, but lysosomal dysfunction was not rescued. Similarly, lysosomal dysfunction, lipid dysregulation, and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Synaptic loss and neurofilament light-chain (NfL) levels, a biomarker for neurodegeneration, were further elevated in the Grn/Trem2 KO cerebrospinal fluid (CSF). These findings suggest that TREM2-dependent microglia hyperactivation in models of GRN deficiency does not promote neurotoxicity, but rather neuroprotection.
Klumpe, S., Fung, H.K., Goetz, S.K., Zagoriy, I., Hampoelz, B., Zhang, X., Erdmann, P.S., Baumbach, J., Müller, C.W., Beck, M., Plitzko, J.M., and Mahamid, J.
Elife, 2021, 10.
DOI: 10.7554/eLife.70506
A modular platform for automated cryo-FIB workflows
Lamella micromachining by focused ion beam milling at cryogenic temperature (cryo-FIB) has matured into a preparation method widely used for cellular cryo-electron tomography. Due to the limited ablation rates of low Ga(+) ion beam currents required to maintain the structural integrity of vitreous specimens, common preparation protocols are time-consuming and labor intensive. The improved stability of new-generation cryo-FIB instruments now enables automated operations. Here, we present an open-source software tool, SerialFIB, for creating automated and customizable cryo-FIB preparation protocols. The software encompasses a graphical user interface for easy execution of routine lamellae preparations, a scripting module compatible with available Python packages, and interfaces with three-dimensional correlative light and electron microscopy (CLEM) tools. SerialFIB enables the streamlining of advanced cryo-FIB protocols such as multi-modal imaging, CLEM-guided lamella preparation and in situ lamella lift-out procedures. Our software therefore provides a foundation for further development of advanced cryogenic imaging and sample preparation protocols.
Congratulations on your PhD!
Friederike Pennemann
Antiviral properties of species conserved nucleic acid-binding proteins
RG: Andreas Pichlmair
Congratulations on your PhD!
Laura Lindenthal
Interaction of macrophages and diseased cells
RG: Peter Murray
Pennemann, F.L., Mussabekova, A., Urban, C., Stukalov, A., Andersen, L.L., Grass, V., Lavacca, T.M., Holze, C., Oubraham, L., Benamrouche, Y., Girardi, E., Boulos, R.E., Hartmann, R., Superti-Furga, G., Habjan, M., Imler, J.L., Meignin, C., and Pichlmair, A.
(IMPRS-LS students are in bold)
Nat Commun, 2021, 12, 7009.
DOI: 10.1038/s41467-021-27192-w
Cross-species analysis of viral nucleic acid interacting proteins identifies TAOKs as innate immune regulators
The cell intrinsic antiviral response of multicellular organisms developed over millions of years and critically relies on the ability to sense and eliminate viral nucleic acids. Here we use an affinity proteomics approach in evolutionary distant species (human, mouse and fly) to identify proteins that are conserved in their ability to associate with diverse viral nucleic acids. This approach shows a core of orthologous proteins targeting viral genetic material and species-specific interactions. Functional characterization of the influence of 181 candidates on replication of 6 distinct viruses in human cells and flies identifies 128 nucleic acid binding proteins with an impact on virus growth. We identify the family of TAO kinases (TAOK1, -2 and -3) as dsRNA-interacting antiviral proteins and show their requirement for type-I interferon induction. Depletion of TAO kinases in mammals or flies leads to an impaired response to virus infection characterized by a reduced induction of interferon stimulated genes in mammals and impaired expression of srg1 and diedel in flies. Overall, our study shows a larger set of proteins able to mediate the interaction between viral genetic material and host factors than anticipated so far, attesting to the ancestral roots of innate immunity and to the lineage-specific pressures exerted by viruses.