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Rüdiger Klein receives an ERC Advanced Grant to analyze the development of amygdala circuits

The amygdala is important for the emotional evaluation of situations or objects. Aided by the amygdala, we are able learn to treat something with affection or aversion. How the amygdala controls the various behavioral reactions and which other brain regions are involved, remains unclear. In order to fill this gap in our knowledge, Rüdiger Klein attempts to specifically reorganize the development of the amygdala circuits in mice, thereby transforming innate and learned emotional behavior. The European Research Council (ERC) is funding this innovative project with a 2.5 million Euro grant over the next five years. Fear protects us from danger, but can also stand in our way when it becomes irrational. A good feeling from eating encourages us to choose suitable food, but can also contribute to eating disorders. No matter whether it is fear, pleasure or other emotions, neurons in the amygdala link our feelings with internal and external stimuli and thereby control our unconscious behavior.

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Kober-Hasslacher, M., Oh-Strauß, H., Kumar, D., Soberón, V., Diehl, C., Lech, M., Engleitner, T., Katab, E., Fernandez Saiz, V., Piontek, G., Li, H., Menze, B., Ziegenhain, C., Enard, W., Rad, R., Böttcher, J.P., Anders, H.J., Rudelius, M., Schmidt-Supprian, M. (IMPRS-LS students are in bold)
J Clin Invest, 2020, [Epub ahead of print].
DOI: 10.1172/JCI124382

c-Rel gain in B cells drives germinal center reactions and autoantibody production

Single nucleotide polymorphisms and locus amplification link the NF-κB transcription factor c-Rel to human autoimmune diseases and B cell lymphomas, respectively. However, the functional consequences of enhanced c-Rel levels remain enigmatic. Here, we overexpressed c-Rel specifically in mouse B cells from BAC-transgenic gene loci and demonstrate that c-Rel protein levels linearly dictated expansion of germinal center (GC) B cells and isotype-switched plasma cells. c-Rel expression in B cells of otherwise c-Rel-deficient mice fully rescued terminal B cell differentiation, underscoring its critical B cell-intrinsic roles. Unexpectedly, in GCB cells transcription-independent regulation produced the highest c-Rel protein levels amongst B cell subsets. In c-Rel overexpressing GCB cells this caused enhanced nuclear translocation, a profoundly altered transcriptional program and increased proliferation. Finally, we provide a link between c-Rel gain and autoimmunity by showing that c-Rel overexpression in B cells caused autoantibody production and renal immune complex deposition.


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Irene Riera Tur
Artificial amyloid-like aggregating proteins cause cytotoxicity in vitro and in vivo
RG: Rüdiger Klein



 

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Libicher, K., Hornberger, R., Heymann, M., and Mutschler, H.
Nat Commun, 2020, 11, 904.
doi: 10.1038/s41467-020-14694-2

In vitro self-replication and multicistronic expression of large synthetic genomes

The generation of a chemical system capable of replication and evolution is a key objective of synthetic biology. This could be achieved by in vitro reconstitution of a minimal self-sustaining central dogma consisting of DNA replication, transcription and translation. Here, we present an in vitro translation system, which enables self-encoded replication and expression of large DNA genomes under well-defined, cell-free conditions. In particular, we demonstrate self-replication of a multipartite genome of more than 116 kb encompassing the full set of Escherichia coli translation factors, all three ribosomal RNAs, an energy regeneration system, as well as RNA and DNA polymerases. Parallel to DNA replication, our system enables synthesis of at least 30 encoded translation factors, half of which are expressed in amounts equal to or greater than their respective input levels. Our optimized cell-free expression platform could provide a chassis for the generation of a partially self-replicating in vitro translation system.


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Baek, K., Krist, D.T., Prabu, J.R., Hill, S., Klügel, M., Neumaier, L.-M., von Gronau, S., Kleiger, G., and Schulman, B.A.
Nature, 2020 578, 461-466.
doi: 10.1038/s41586-020-2000-y

NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly

Eukaryotic cell biology depends on cullin-RING E3 ligase (CRL)-catalysed protein ubiquitylation, which is tightly controlled by the modification of cullin with the ubiquitin-like protein NEDD8. However, how CRLs catalyse ubiquitylation, and the basis of NEDD8 activation, remain unknown. Here we report the cryo-electron microscopy structure of a chemically trapped complex that represents the ubiquitylation intermediate, in which the neddylated CRL1β-TRCP promotes the transfer of ubiquitin from the E2 ubiquitin-conjugating enzyme UBE2D to its recruited substrate, phosphorylated IκBα. NEDD8 acts as a nexus that binds disparate cullin elements and the RING-activated ubiquitin-linked UBE2D. Local structural remodelling of NEDD8 and large-scale movements of CRL domains converge to juxtapose the substrate and the ubiquitylation active site. These findings explain how a distinctive ubiquitin-like protein alters the functions of its targets, and show how numerous NEDD8-dependent interprotein interactions and conformational changes synergistically configure a catalytic CRL architecture that is both robust, to enable rapid ubiquitylation of the substrate, and fragile, to enable the subsequent functions of cullin-RING proteins.


graduationCongratulations on your PhD!

Yunmin Wu
Neural Basis of Visual Motion Perception: An Illusory Perspective
RG: Herwig Baier

Mahesh Lingaraju
Structural and Biochemical Characterization of Interactions Centered on RNA Decay Factors: MTR4 and SMG1
RG: Elena Conti


 

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Lee, C.-W., Wilfling, F., Ronchi, P., Allegretti, M., Mosalaganti, S., Jentsch, S., Beck, M., and Pfander, B.
Nat Cell Biol, 2020 22, 159-166.
doi: 10.1038/s41556-019-0459-2

Selective autophagy degrades nuclear pore complexes

Nuclear pore complexes (NPCs) are very large proteinaceous assemblies that consist of more than 500 individual proteins1,2. NPCs are essential for nucleocytoplasmic transport of different cellular components, and disruption of the integrity of NPCs has been linked to aging, cancer and neurodegenerative diseases3-7. However, the mechanism by which membrane-embedded NPCs are turned over is currently unknown. Here we show that, after nitrogen starvation or genetic interference with the architecture of NPCs, nucleoporins are rapidly degraded in the budding yeast Saccharomyces cerevisiae. We demonstrate that NPC turnover involves vacuolar proteases and the core autophagy machinery. Autophagic degradation is mediated by the cytoplasmically exposed Nup159, which serves as intrinsic cargo receptor and directly binds to the autophagy marker protein Atg8. Autophagic degradation of NPCs is therefore inducible, enabling the removal of individual NPCs from the nuclear envelope.


Identification of a protein complex that attracts or repels nerve cells during development

The three proteins Teneurin, Latrophilin and FLRT hold together and bring neighboring neurons into close contact, enabling the formation of synapses and the exchange of information between the cells. In the early phase of brain development, however, the interaction of the same proteins leads to the repulsion of migrating nerve cells, as researchers from the Max Planck Institute of Neurobiology and the University of Oxford have now shown. The detailed insight into the molecular guidance mechanisms of brain cells was possible due to the structural analyses of the protein complex.

Well anchored, the proteins Teneurin and FLRT are located on the surface of nerve cells. They are on the lookout for their partner protein, Latrophilin, on other neurons. When the three proteins come into contact, they interconnect and hold the membranes together. They then trigger still largely unknown signaling cascades and thus promote the formation of a synapse at this site. Teneurin and its partner proteins are known to establish these important cell contacts in the brain. Teneurin is also an evolutionary very old protein, with related proteins found in diverse organisms ranging from bacteria to worms, fruit flies and vertebrates. However, the role of these proteins during brain development, when neurons are not yet forming synapses, remained unknown.

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graduation
Congratulations on your PhD!


Samira Parhizkar
Loss of TREM2 function increases amyloid seeding but reduces plaque associated ApoE
RG: Christian Haass



 

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Hergenhan S, Holtkamp S, and Scheiermann C.
J Mol Biol. 2020;S0022-2836(20)30028-0.
(*IMPRS-LS students are in bold)
doi:10.1016/j.jmb.2019.12.044

Molecular interactions between components of the circadian clock and the immune system

The immune system is under control of the circadian clock. Many of the circadian rhythms observed in the immune system originate in direct interactions between components of the circadian clock and components of the immune system. The main means of circadian control over the immune system is by direct control of circadian clock proteins acting as transcription factors driving the expression or repression of immune genes. A second circadian control of immunity lies in the acetylation or methylation of histones to regulate gene transcription or inflammatory proteins. Furthermore, circadian clock proteins can engage in direct physical interactions with components of key inflammatory pathways such as members of the NFκB protein family. This regulation is transcription independent and allows the immune system to also reciprocally exert control over circadian clock function. Thus, the molecular interactions between the circadian clock and the immune system are manifold. We highlight and discuss here the recent findings with respect to the molecular mechanisms that control time-of-day dependent immunity. This review provides a structured overview focusing on the key circadian clock proteins and discusses their reciprocal interactions with the immune system.