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Jocher, G., Grass, V., Tschirner, S.K., Riepler, L., Breimann, S., Kaya, T., Oelsner, M., Hamad, M.S., Hofmann, L.I., Blobel, C.P., Schmidt-Weber, C.B., Gokce, O., Jakwerth, C.A., Trimpert, J., Kimpel, J., Pichlmair, A., and Lichtenthaler, S.F.
EMBO reports, 2022, e54305.
doi: 10.15252/embr.202154305

ADAM10 and ADAM17 promote SARS-CoV-2 cell entry and spike protein-mediated lung cell fusion

The severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) is the causative agent of COVID-19, but host cell factors contributing to COVID-19 pathogenesis remain only partly understood. We identify the host metalloprotease ADAM17 as a facilitator of SARS-CoV-2 cell entry and the metalloprotease ADAM10 as a host factor required for lung cell syncytia formation, a hallmark of COVID-19 pathology. ADAM10 and ADAM17, which are broadly expressed in the human lung, cleave the SARS-CoV-2 spike protein (S) in vitro, indicating that ADAM10 and ADAM17 contribute to the priming of S, an essential step for viral entry and cell fusion. ADAM protease-targeted inhibitors severely impair lung cell infection by the SARS-CoV-2 variants of concern alpha, beta, delta, and omicron and also reduce SARS-CoV-2 infection of primary human lung cells in a TMPRSS2 protease-independent manner. Our study establishes ADAM10 and ADAM17 as host cell factors for viral entry and syncytia formation and defines both proteases as potential targets for antiviral drug development.

 


 

graduationCongratulations on your PhD!

Jakub Chrustowicz


Mechanistic studies of GID/CTLH E3 ubiquitin ligases   

RG: Brenda Schulman

 


 

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Hees, J.T., and Harbauer, A.B.
Methods Mol Biol, 2022, 2431, 225-237.
doi: 10.1007/978-1-0716-1990-2_11

Live-Cell Imaging of RNA Transport in Axons of Cultured Primary Neurons

The use of fluorescent proteins has revolutionized the study of protein localization and transport. However, the visualization of other molecules and specifically RNA during live-cell imaging remains challenging. In this chapter, we provide guidance to the available methods, their advantages and drawbacks as well as provide a detailed protocol for the detection of RNA transport using the MS2/PP7-split-Venus system for background-free RNA imaging.

 


 

graduationCongratulations on your PhD!

Sebastian Kostrhon


Cryo-EM structure of CUL5-ARIH2 E3-E3 ligase complex reveals novel allosteric NEDD8 mechanism  

RG: Brenda Schulman

 


 

Neurons are constantly performing complex calculations to process sensory information and infer the state of the environment. For example, to localize a sound or to recognize the direction of visual motion, individual neurons are thought to multiply two signals. However, how such a computation is carried out has been a mystery for decades. Researchers at the Max Planck Institute for Biological Intelligence, in foundation (i.f.), have now discovered in fruit flies the biophysical basis that enables a specific type of neuron to multiply two incoming signals. This provides fundamental insights into the algebra of neurons – the computations that may underlie countless processes in the brain.

We easily recognize objects and the direction in which they move. The brain calculates this information based on local changes in light intensity detected by our retina. The calculations occur at the level of individual neurons. But what does it mean when neurons calculate? In a network of communicating nerve cells, each cell must calculate its outgoing signal based on a multitude of incoming signals. Certain types of signal will increase and others will reduce the outgoing signal – processes that neuroscientists refer to as 'excitation' and 'inhibition'. 

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Researchers at the MPI of Biochemistry, together with collaborating partners, have discovered the first proteomic subtype of an aggressive blood cancer known as acute myeloid leukemia by using mass spectrometry technology.

In order to better treat patients diagnosed with acute myeloid leukemia (AML), the pathological processes and also existing subtypes of the disease must be better understood. With the help of proteome and genome analysis, researchers at the Max Planck Institute (MPI) of Biochemistry in Martinsried, together with cooperation partners from the University Hospital in Frankfurt am Main, have discovered a new subtype. This subgroup contains elevated levels of mitochondrial proteins and thus has altered mitochondrial metabolism. These so-called mito-AML cells can be combated more effectively in laboratory experiments with the help of inhibitors against mitochondrial respiration than with conventional chemotherapeutic agents. The study was published in Cancer Cell.

Identification of molecular AML subtypes

Acute myeloid leukemia (AML) is an aggressive cancer originating from blood cells. When immature blood cells in the bone marrow acquire certain aberrations in their genome they become malignant and overgrow the bone marrow, the place where normally blood cells are produced. As a consequence, normal blood cells are suppressed by the leukemia cells and this leads to infections, bleeding and ultimately death of patients. Most patients diagnosed with AML undergo chemotherapy. In the last decades genomic studies identified molecular subtypes of the disease thereby opening up a perspective for personalized therapeutic approaches in AML. As a result, Clinicians and researchers now distinguish different genomic AML subtypes and for some of them they now even use specific therapeutics. These discoveries have certainly revolutionized the molecular understanding of the disease. However, despite this progress, prognosis for AML remains poor, highlighting the strong medical need for a deeper understanding of AML pathophysiology and for further innovative and more efficient therapies. 

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graduationCongratulations on your PhD!

Mai Ly Tran


Mechanisms of secretory cargo sorting at the trans-Golgi network  

RG: Julia von Blume

 


 

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Scherr, M.J., Wahab, S.A., Remus, D., and Duderstadt, K.E.
Cell Rep, 2022, 38, 110531.
doi: 10.1016/j.celrep.2022.110531

Mobile origin-licensing factors confer resistance to conflicts with RNA polymerase

Fundamental to our understanding of chromosome duplication is the idea that replication origins function both as sites where MCM helicases are loaded during the G1 phase and where synthesis begins in S phase. However, the temporal delay between phases exposes the replisome assembly pathway to potential disruption prior to replication. Using multicolor, single-molecule imaging, we systematically study the consequences of encounters between actively transcribing RNA polymerases (RNAPs) and replication initiation intermediates in the context of chromatin. We demonstrate that RNAP can push multiple licensed MCM helicases over long distances with nucleosomes ejected or displaced. Unexpectedly, we observe that MCM helicase loading intermediates also can be repositioned by RNAP and continue origin licensing after encounters with RNAP, providing a web of alternative origin specification pathways. Taken together, our observations reveal a surprising mobility in origin-licensing factors that confers resistance to the complex challenges posed by diverse obstacles encountered on chromosomes.

 


 

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Weickert, P., and Stingele, J.
Annu Rev Biochem, 2022, online ahead of print.
doi: 10.1146/annurev-biochem-032620-105820

DNA-Protein Crosslinks and Their Resolution

Covalent DNA-protein crosslinks (DPCs) are pervasive DNA lesions that interfere with essential chromatin processes such as transcription or replication. This review strives to provide an overview of the sources and principles of cellular DPC formation. DPCs are caused by endogenous reactive metabolites and various chemotherapeutic agents. However, in certain conditions DPCs also arise physiologically in cells. We discuss the cellular mechanisms resolving these threats to genomic integrity. Detection and repair of DPCs require not only the action of canonical DNA repair pathways but also the activity of specialized proteolytic enzymes-including proteases of the SPRTN/Wss1 family-to degrade the crosslinked protein. Loss of DPC repair capacity has dramatic consequences, ranging from genome instability in yeast and worms to cancer predisposition and premature aging in mice and humans.

 


 

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Unterauer, E.M., and Jungmann, R.
Front Synaptic Neurosci, 2022, 13, 798267.
doi: 10.3389/fnsyn.2021.798267

Quantitative Imaging With DNA-PAINT for Applications in Synaptic Neuroscience

Super-resolution (SR) microscopy techniques have been advancing the understanding of neuronal protein networks and interactions. Unraveling the arrangement of proteins with molecular resolution provided novel insights into neuron cytoskeleton structure and actin polymerization dynamics in synaptic spines. Recent improvements in quantitative SR imaging have been applied to synaptic protein clusters and with improved multiplexing technology, the interplay of multiple protein partners in synaptic active zones has been elucidated. While all SR techniques come with benefits and drawbacks, true molecular quantification is a major challenge with the most complex requirements for labeling reagents and careful experimental design. In this perspective, we provide an overview of quantitative SR multiplexing and discuss in greater detail the quantification and multiplexing capabilities of the SR technique DNA-PAINT. Using predictable binding kinetics of short oligonucleotides, DNA-PAINT provides two unique approaches to address multiplexed molecular quantification: qPAINT and Exchange-PAINT. With precise and accurate quantification and spectrally unlimited multiplexing, DNA-PAINT offers an attractive route to unravel complex protein interaction networks in neurons. Finally, while the SR community has been pushing technological advances from an imaging technique perspective, the development of universally available, small, efficient, and quantitative labels remains a major challenge in the field.