Congratulations on your PhD!
Ksenia Finogenova
Structural basis of nucleosome binding by PRC2 and its regulation by histone modifications
RG: Jürg Müller
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Tüshaus, J., Kataka, E.S., Zaucha, J., Frishman, D., Müller, S.A., and Lichtenthaler, S.F.
Proteomics, 2021, 21, e2000174.
doi: 10.1002/pmic.202000174
Neuronal Differentiation of LUHMES Cells Induces Substantial Changes of the Proteome
Neuronal cell lines are important model systems to study mechanisms of neurodegenerative diseases. One example is the Lund Human Mesencephalic (LUHMES) cell line, which can differentiate into dopaminergic-like neurons and is frequently used to study mechanisms of Parkinson's disease and neurotoxicity. Neuronal differentiation of LUHMES cells is commonly verified with selected neuronal markers, but little is known about the proteome-wide protein abundance changes during differentiation. Using mass spectrometry and label-free quantification (LFQ), the proteome of differentiated and undifferentiated LUHMES cells and of primary murine midbrain neurons are compared. Neuronal differentiation induced substantial changes of the LUHMES cell proteome, with proliferation-related proteins being strongly down-regulated and neuronal and dopaminergic proteins, such as L1CAM and α-synuclein (SNCA) being up to 1,000-fold up-regulated. Several of these proteins, including MAPT and SYN1, may be useful as new markers for experimentally validating neuronal differentiation of LUHMES cells. Primary midbrain neurons are slightly more closely related to differentiated than to undifferentiated LUHMES cells, in particular with respect to the abundance of proteins related to neurodegeneration. In summary, the analysis demonstrates that differentiated LUHMES cells are a suitable model for studies on neurodegeneration and provides a resource of the proteome-wide changes during neuronal differentiation. (ProteomeXchange identifier PXD020044).
Tüshaus, J., Müller, S.A., Shrouder, J., Arends, M., Simons, M., Plesnila, N., Blobel, C.P., and Lichtenthaler, S.F
FASEB J, 2021, 35, e21962
doi: 10.1096/fj.202100936R
The pseudoprotease iRhom1 controls ectodomain shedding of membrane proteins in the nervous system
Proteolytic ectodomain shedding of membrane proteins is a fundamental mechanism to control the communication between cells and their environment. A key protease for membrane protein shedding is ADAM17, which requires a non-proteolytic subunit, either inactive Rhomboid 1 (iRhom1) or iRhom2 for its activity. While iRhom1 and iRhom2 are co-expressed in most tissues and appear to have largely redundant functions, the brain is an organ with predominant expression of iRhom1. Yet, little is known about the spatio-temporal expression of iRhom1 in mammalian brain and about its function in controlling membrane protein shedding in the nervous system. Here, we demonstrate that iRhom1 is expressed in mouse brain from the prenatal stage to adulthood with a peak in early postnatal development. In the adult mouse brain iRhom1 was widely expressed, including in cortex, hippocampus, olfactory bulb, and cerebellum. Proteomic analysis of the secretome of primary neurons using the hiSPECS method and of cerebrospinal fluid, obtained from iRhom1-deficient and control mice, identified several membrane proteins that require iRhom1 for their shedding in vitro or in vivo. One of these proteins was 'multiple-EGF-like-domains protein 10' (MEGF10), a phagocytic receptor in the brain that is linked to the removal of amyloid β and apoptotic neurons. MEGF10 was further validated as an ADAM17 substrate using ADAM17-deficient mouse embryonic fibroblasts. Taken together, this study discovers a role for iRhom1 in controlling membrane protein shedding in the mouse brain, establishes MEGF10 as an iRhom1-dependent ADAM17 substrate and demonstrates that iRhom1 is widely expressed in murine brain.
Congratulations on your PhD!
Özge Karayel Eren
Development of sensitive and quantitative proteomics strategies to study phospho- and ubiquitin-signaling in health and disease
RG: Matthias Mann
The Max Planck Society has succeeded in recruiting two renowned scientists. Kikuë Tachibana and John Briggs will now be conducting their research at the MPI of Biochemistry in Martinsried.
The Max Planck Institute of Biochemistry (MPIB) expands its scientific expertise with two new directors: Kikuë Tachibana and John Briggs. Molecular geneticist Kikuë Tachibana has moved with her research group from Vienna to Martinsried. Since August 1, she heads the research department "Totipotency". Together with her team, she studies cells that have the ability to develop into whole organisms. In parallel, structural biologist John Briggs starts his work at the institute. He has moved from Cambridge, UK, to Martinsried and heads the department "Cell and Virus Structure" since September 1. John Briggs and his team will study the structures of viruses as well as fundamental molecular cellular mechanisms.
Martinsried - since August 1 and September 1, respectively, Dr. Kikuë Tachibana and Dr. John Briggs are new full-time directors at MPIB. With the two new researchers, the institute now has nine directors, sharpening the research profile of the Max Planck Society. The new director Tachibana says: “I am delighted to have the opportunity offered by the Max Planck Society to devote our research to uncover the molecular mechanisms underlying the start of life. I am looking forward to collaborate scientifically with my colleagues and to work together for developing the Martinsried campus." John Briggs explains, "Structural biology and method development in microscopy have a long tradition in Martinsried. My team and I, together with our new colleagues in Martinsried, are looking forward to finding out more about how viruses assemble and how they function."
New mouse type reveals when neurons fail to cope with misfolded proteins.
Proteins are the "tools" of our cells – they are essential to all vital tasks. However, they are only able to do their jobs if they fold correctly and adopt their respective, very specific 3D structure. To ensure that nothing goes wrong with the folding process, it is strictly monitored in the cell. The consequences of a flawed quality control can be seen, for example, in the deposition of misfolded proteins in neurodegenerative diseases such as Alzheimer's. Researchers at the Max Planck Institutes of Neurobiology and of Biochemistry have now developed a mouse line that makes the state of protein balance visible in the mammalian brain for the first time. In this way, the processes of protein quality control can now be studied in healthy and diseased neurons in more detail.
Proteins fulfill all important tasks in our body: They transport substances, protect against diseases, support the cell and catalyze chemical reactions – to name just a few. With the building instructions in our genetic code, every protein can be produced as a long chain of amino acids. However, that's not the end of the story: in order to perform their vital functions, proteins have to fold into complex 3D structures.
Each cell contains a whole machinery that helps proteins to fold, corrects folding errors and discards misfolded proteins. As a kind of quality control, the system thus contributes to proteostasis – the controlled function of all proteins.
Merino-Salomón, A., Babl, L., and Schwille, P.
Curr Opin Cell Biol, 2021, 72, 106-115, online ahead of print.
doi: 10.1016/j.ceb.2021.07.001
Self-organized protein patterns: The MinCDE and ParABS systems
Self-organized protein patterns are of tremendous importance for biological decision-making processes. Protein patterns have been shown to identify the site of future cell division, establish cell polarity, and organize faithful DNA segregation. Intriguingly, several key concepts of pattern formation and regulation apply to a variety of different protein systems. Herein, we explore recent advances in the understanding of two prokaryotic pattern-forming systems: the MinCDE system, positioning the FtsZ ring precisely at the midcell, and the ParABS system, distributing newly synthesized DNA along with the cell. Despite differences in biological functionality, these two systems have remarkably similar molecular components, mechanisms, and strategies to achieve biological robustness.
Murali Mahadevan, H., Hashemiaghdam, A., Ashrafi, G., and Harbauer, A.B.
Adv Biol (Weinh), 2021, e2100663, online ahead of print.
doi: 10.1002/adbi.202100663
Mitochondria in Neuronal Health: From Energy Metabolism to Parkinson's Disease
Mitochondria are the main suppliers of neuronal adenosine triphosphate and play a critical role in brain energy metabolism. Mitochondria also serve as Ca2+ sinks and anabolic factories and are therefore essential for neuronal function and survival. Dysregulation of neuronal bioenergetics is increasingly implicated in neurodegenerative disorders, particularly Parkinson's disease. This review describes the role of mitochondria in energy metabolism under resting conditions and during synaptic transmission, and presents evidence for the contribution of neuronal mitochondrial dysfunction to Parkinson's disease.
Frauenstein, A., Ebner, S., Hansen, F.M., Sinha, A., Phulphagar, K., Swatek, K., Hornburg, D., Mann, M., and Meissner, F.
(IMPRS-LS students and alumni students are in bold)
Mol Syst Biol, 2021, 17, e10125.
doi: 10.15252/msb.202010125
Identification of covalent modifications regulating immune signaling complex composition and phenotype
Cells signal through rearrangements of protein communities governed by covalent modifications and reversible interactions of distinct sets of proteins. A method that identifies those post-transcriptional modifications regulating signaling complex composition and functional phenotypes in one experimental setup would facilitate an efficient identification of novel molecular signaling checkpoints. Here, we devised modifications, interactions and phenotypes by affinity purification mass spectrometry (MIP-APMS), comprising the streamlined cloning and transduction of tagged proteins into functionalized reporter cells as well as affinity chromatography, followed by MS-based quantification. We report the time-resolved interplay of more than 50 previously undescribed modification and hundreds of protein-protein interactions of 19 immune protein complexes in monocytes. Validation of interdependencies between covalent, reversible, and functional protein complex regulations by knockout or site-specific mutation revealed ISGylation and phosphorylation of TRAF2 as well as ARHGEF18 interaction in Toll-like receptor 2 signaling. Moreover, we identify distinct mechanisms of action for small molecule inhibitors of p38 (MAPK14). Our method provides a fast and cost-effective pipeline for the molecular interrogation of protein communities in diverse biological systems and primary cells.
Martinelli, S., Anderzhanova, E.A., Bajaj, T., Wiechmann, S., Dethloff, F., Weckmann, K., Heinz, D.E., Ebert, T., Hartmann, J., Geiger, T.M., et al.
(IMPRS-LS students and alumni students are in bold)
Nat Commun, 2021, 12, 4643.
doi: 10.1038/s41467-021-24810-5
Stress-primed secretory autophagy promotes extracellular BDNF maturation by enhancing MMP9 secretion
The stress response is an essential mechanism for maintaining homeostasis, and its disruption is implicated in several psychiatric disorders. On the cellular level, stress activates, among other mechanisms, autophagy that regulates homeostasis through protein degradation and recycling. Secretory autophagy is a recently described pathway in which autophagosomes fuse with the plasma membrane rather than with lysosomes. Here, we demonstrate that glucocorticoid-mediated stress enhances secretory autophagy via the stress-responsive co-chaperone FK506-binding protein 51. We identify the matrix metalloproteinase 9 (MMP9) as one of the proteins secreted in response to stress. Using cellular assays and in vivo microdialysis, we further find that stress-enhanced MMP9 secretion increases the cleavage of pro-brain-derived neurotrophic factor (proBDNF) to its mature form (mBDNF). BDNF is essential for adult synaptic plasticity and its pathway is associated with major depression and posttraumatic stress disorder. These findings unravel a cellular stress adaptation mechanism that bears the potential of opening avenues for the understanding of the pathophysiology of stress-related disorders.