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Article ; Online: Proteasomal turnover of the RhoGAP tumor suppressor DLC1 is regulated by HECTD1 and USP7

Yannick Frey / Mirita Franz-Wachtel / Boris Macek / Monilola A. Olayioye

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 10

Abstract: Abstract The Rho GTPase activating protein Deleted in Liver Cancer 1 (DLC1) is frequently downregulated through genetic and epigenetic mechanisms in various malignancies, leading to aberrant Rho GTPase signaling and thus facilitating cancer progression. ... ...

Abstract	Abstract The Rho GTPase activating protein Deleted in Liver Cancer 1 (DLC1) is frequently downregulated through genetic and epigenetic mechanisms in various malignancies, leading to aberrant Rho GTPase signaling and thus facilitating cancer progression. Here we show that in breast cancer cells, dysregulation of DLC1 expression occurs at the protein level through rapid degradation via the ubiquitin–proteasome system. Using mass spectrometry, we identify two novel DLC1 interaction partners, the ubiquitin-ligase HECTD1 and the deubiquitinating enzyme ubiquitin-specific-processing protease 7 (USP7). While DLC1 protein expression was rapidly downregulated upon pharmacological inhibition of USP7, siRNA-mediated knockdown of HECTD1 increased DLC1 protein levels and impaired its degradation. Immunofluorescence microscopy analyses revealed that the modulation of HECTD1 levels and USP7 activity altered DLC1 abundance at focal adhesions, its primary site of action. Thus, we propose opposing regulatory mechanisms of DLC1 protein homeostasis by USP7 and HECTD1, which could open up strategies to counteract downregulation and restore DLC1 expression in cancer.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Histone 4 lysine 5/12 acetylation enables developmental plasticity of Pristionchus mouth form

Michael S. Werner / Tobias Loschko / Thomas King / Shelley Reich / Tobias Theska / Mirita Franz-Wachtel / Boris Macek / Ralf J. Sommer

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 14

Abstract: Abstract Development can be altered to match phenotypes with the environment, and the genetic mechanisms that direct such alternative phenotypes are beginning to be elucidated. Yet, the rules that govern environmental sensitivity vs. invariant ... ...

Abstract	Abstract Development can be altered to match phenotypes with the environment, and the genetic mechanisms that direct such alternative phenotypes are beginning to be elucidated. Yet, the rules that govern environmental sensitivity vs. invariant development, and potential epigenetic memory, remain unknown. Here, we show that plasticity of nematode mouth forms is determined by histone 4 lysine 5 and 12 acetylation (H4K5/12ac). Acetylation in early larval stages provides a permissive chromatin state, which is susceptible to induction during the critical window of environmental sensitivity. As development proceeds deacetylation shuts off switch gene expression to end the critical period. Inhibiting deacetylase enzymes leads to fixation of prior developmental trajectories, demonstrating that histone modifications in juveniles can carry environmental information to adults. Finally, we provide evidence that this regulation was derived from an ancient mechanism of licensing developmental speed. Altogether, our results show that H4K5/12ac enables epigenetic regulation of developmental plasticity that can be stored and erased by acetylation and deacetylation, respectively.
Keywords	Science ; Q
Subject code	572
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: An interaction network of RNA-binding proteins involved in Drosophila oogenesis

Prashali Bansal / Johannes Madlung / Kristina Schaaf / Boris Macek / Fulvia Bono

Abstract: AbstractDuring Drosophila oogenesis, the localization and translational regulation of maternal transcripts relies on RNA-binding proteins (RBPs). Many of these RBPs localize several mRNAs and may have additional direct interaction partners to regulate ... ...

Abstract	AbstractDuring Drosophila oogenesis, the localization and translational regulation of maternal transcripts relies on RNA-binding proteins (RBPs). Many of these RBPs localize several mRNAs and may have additional direct interaction partners to regulate their functions. Using immunoprecipitation from whole Drosophila ovaries coupled to mass spectrometry, we examined protein-protein associations of 6 GFP-tagged RBPs expressed at physiological levels. Analysis of the interaction network and further validation in human cells allowed us to identify 26 previously unknown associations, besides recovering several well characterized interactions. We identified interactions between RBPs and several splicing factors, providing links between nuclear and cytoplasmic events of mRNA regulation. Additionally, components of the translational and RNA decay machineries were selectively co-purified with some baits, suggesting a mechanism for how RBPs may regulate maternal transcripts. Given the evolutionary conservation of the studied RBPs, the interaction network presented here provides the foundation for future functional and structural studies of mRNA localization across metazoans.
Keywords	covid19
Publisher	biorxiv
Document type	Article ; Online
DOI	10.1101/2020.01.08.899146
Database	COVID19

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Article ; Online: A Nanobody-Based Toolset to Monitor and Modify the Mitochondrial GTPase Miro1

Funmilayo O. Fagbadebo / Philipp D. Kaiser / Katharina Zittlau / Natascha Bartlick / Teresa R. Wagner / Theresa Froehlich / Grace Jarjour / Stefan Nueske / Armin Scholz / Bjoern Traenkle / Boris Macek / Ulrich Rothbauer

Frontiers in Molecular Biosciences, Vol

2022 Volume 9

Abstract: The mitochondrial outer membrane (MOM)-anchored GTPase Miro1, is a central player in mitochondrial transport and homeostasis. The dysregulation of Miro1 in amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) suggests that Miro1 may be a ... ...

Abstract	The mitochondrial outer membrane (MOM)-anchored GTPase Miro1, is a central player in mitochondrial transport and homeostasis. The dysregulation of Miro1 in amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) suggests that Miro1 may be a potential biomarker or drug target in neuronal disorders. However, the molecular functionality of Miro1 under (patho-) physiological conditions is poorly known. For a more comprehensive understanding of the molecular functions of Miro1, we have developed Miro1-specific nanobodies (Nbs) as novel research tools. We identified seven Nbs that bind either the N- or C-terminal GTPase domain of Miro1 and demonstrate their application as research tools for proteomic and imaging approaches. To visualize the dynamics of Miro1 in real time, we selected intracellularly functional Nbs, which we reformatted into chromobodies (Cbs) for time-lapse imaging of Miro1. By genetic fusion to an Fbox domain, these Nbs were further converted into Miro1-specific degrons and applied for targeted degradation of Miro1 in live cells. In summary, this study presents a collection of novel Nbs that serve as a toolkit for advanced biochemical and intracellular studies and modulations of Miro1, thereby contributing to the understanding of the functional role of Miro1 in disease-derived model systems.
Keywords	Miro1 ; nanobodies ; imaging ; proteomics ; degron ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A network of cytosolic (co)chaperones promotes the biogenesis of mitochondrial signal-anchored outer membrane proteins

Layla Drwesh / Benjamin Heim / Max Graf / Linda Kehr / Lea Hansen-Palmus / Mirita Franz-Wachtel / Boris Macek / Hubert Kalbacher / Johannes Buchner / Doron Rapaport

eLife, Vol

2022 Volume 11

Abstract: Signal-anchored (SA) proteins are anchored into the mitochondrial outer membrane (OM) via a single transmembrane segment at their N-terminus while the bulk of the proteins is facing the cytosol. These proteins are encoded by nuclear DNA, translated on ... ...

Abstract	Signal-anchored (SA) proteins are anchored into the mitochondrial outer membrane (OM) via a single transmembrane segment at their N-terminus while the bulk of the proteins is facing the cytosol. These proteins are encoded by nuclear DNA, translated on cytosolic ribosomes, and are then targeted to the organelle and inserted into its OM by import factors. Recently, research on the insertion mechanisms of these proteins into the mitochondrial OM have gained a lot of attention. In contrast, the early cytosolic steps of their biogenesis are unresolved. Using various proteins from this category and a broad set of in vivo, in organello, and in vitro assays, we reconstituted the early steps of their biogenesis. We identified a subset of molecular (co)chaperones that interact with newly synthesized SA proteins, namely, Hsp70 and Hsp90 chaperones and co-chaperones from the Hsp40 family like Ydj1 and Sis1. These interactions were mediated by the hydrophobic transmembrane segments of the SA proteins. We further demonstrate that interfering with these interactions inhibits the biogenesis of SA proteins to a various extent. Finally, we could demonstrate direct interaction of peptides corresponding to the transmembrane segments of SA proteins with the (co)chaperones and reconstitute in vitro the transfer of such peptides from the Hsp70 chaperone to the mitochondrial Tom70 receptor. Collectively, this study unravels an array of cytosolic chaperones and mitochondrial import factors that facilitates the targeting and membrane integration of mitochondrial SA proteins.
Keywords	mitochondria ; chaperones ; outer membrane ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2022-07-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comparative Transcriptional Profiling of Motor Neuron Disorder-Associated Genes in Various Human Cell Culture Models

Stefan Hauser / Stefanie Schuster / Elena Heuten / Philip Höflinger / Jakob Admard / Yvonne Schelling / Ana Velic / Boris Macek / Stephan Ossowski / Ludger Schöls

Frontiers in Cell and Developmental Biology, Vol

2020 Volume 8

Abstract: Disease modeling requires appropriate cellular models that best mimic the underlying pathophysiology. Human origin and an adequate expression of the disease protein are pre-requisites that support information from a model to be meaningful. In this study ... ...

Abstract	Disease modeling requires appropriate cellular models that best mimic the underlying pathophysiology. Human origin and an adequate expression of the disease protein are pre-requisites that support information from a model to be meaningful. In this study we investigated expression profiles of (i) PBMCs and (ii) fibroblasts as patient derived cells as well as (iii) lymphoblasts and (iv) induced pluripotent stem cells (iPSC) as immortalized sources, and (v) iPSC-derived cortical neurons to assess their aptitude to model motor neuron diseases (MNDs) including hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). We generated all five different cell types from two healthy donors and performed RNA sequencing to display expression patterns in MND-related genes. For the ten most common HSP genotypes we validated gene expression by qPCR. To verify the results on protein level, proteome analysis of fibroblasts, iPSCs and cortical neurons was performed. Depending on the specific MND gene we found largely different expression patterns. Out of 168 MND-related genes, 50 had their highest expression in iPSC-derived cortical neurons, 41 were most strongly expressed in fibroblasts, 26 in lymphoblasts, 22 in iPSCs, and 14 in PBMCs. Pathophysiologically related MNDs like HSPs associated with axonal transport deficits shared highest expression in cortical neurons. 15 MND-related genes were not detectable in any of the analyzed cell types. This may reflect the critical dependency of motor neurons on support of other cell types like oligodendrocytes which express myelin proteins like L1CAM (SPG1), PLP1 (SPG2) and MAG (SPG75) which are lacking in neurons but cause MNDs if mutated. This study provides comprehensive information on expression of genes associated with a large spectrum of MNDs. Expression profiles can be used to inform on appropriate cell models for genotype specific motor neuron research.
Keywords	motor neuron disorders ; hereditary spastic paraplegia ; amyotrophic lateral sclerosis ; spinal muscular atrophy ; gene expression ; iPSCs ; Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Arabidopsis SAC9 enzyme is enriched in a cortical population of early endosomes and restricts PI(4,5)P2 at the plasma membrane

Alexis Lebecq / Mehdi Doumane / Aurelie Fangain / Vincent Bayle / Jia Xuan Leong / Frédérique Rozier / Maria del Marques-Bueno / Laia Armengot / Romain Boisseau / Mathilde Laetitia Simon / Mirita Franz-Wachtel / Boris Macek / Suayib Üstün / Yvon Jaillais / Marie-Cécile Caillaud

eLife, Vol

2022 Volume 11

Abstract: Membrane lipids, and especially phosphoinositides, are differentially enriched within the eukaryotic endomembrane system. This generates a landmark code by modulating the properties of each membrane. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] ... ...

Abstract	Membrane lipids, and especially phosphoinositides, are differentially enriched within the eukaryotic endomembrane system. This generates a landmark code by modulating the properties of each membrane. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] specifically accumulates at the plasma membrane in yeast, animal, and plant cells, where it regulates a wide range of cellular processes including endocytic trafficking. However, the functional consequences of mispatterning PI(4,5)P2 in plants are unknown. Here, we functionally characterized the putative phosphoinositide phosphatase SUPPRESSOR OF ACTIN9 (SAC9) in Arabidopsis thaliana (Arabidopsis). We found that SAC9 depletion led to the ectopic localization of PI(4,5)P2 on cortical intracellular compartments, which depends on PI4P and PI(4,5)P2 production at the plasma membrane. SAC9 localizes to a subpopulation of trans-Golgi Network/early endosomes that are enriched in a region close to the cell cortex and that are coated with clathrin. Furthermore, it interacts and colocalizes with Src Homology 3 Domain Protein 2 (SH3P2), a protein involved in endocytic trafficking. In the absence of SAC9, SH3P2 localization is altered and the clathrin-mediated endocytosis rate is reduced. Together, our results highlight the importance of restricting PI(4,5)P2 at the plasma membrane and illustrate that one of the consequences of PI(4,5)P2 misspatterning in plants is to impact the endocytic trafficking.
Keywords	endocytosis ; plasma membrane ; phosphoinositides ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A TOR (target of rapamycin) and nutritional phosphoproteome of fission yeast reveals novel targets in networks conserved in humans

Lenka Halova / David Cobley / Mirita Franz-Wachtel / Tingting Wang / Kaitlin R. Morrison / Karsten Krug / Nicolas Nalpas / Boris Maček / Iain M. Hagan / Sean J. Humphrey / Janni Petersen

Open Biology, Vol 11, Iss

2021 Volume 4

Abstract: Fluctuations in TOR, AMPK and MAP-kinase signalling maintain cellular homeostasis and coordinate growth and division with environmental context. We have applied quantitative, SILAC mass spectrometry to map TOR and nutrient-controlled signalling in the ... ...

Abstract	Fluctuations in TOR, AMPK and MAP-kinase signalling maintain cellular homeostasis and coordinate growth and division with environmental context. We have applied quantitative, SILAC mass spectrometry to map TOR and nutrient-controlled signalling in the fission yeast Schizosaccharomyces pombe. Phosphorylation levels at more than 1000 sites were altered following nitrogen stress or Torin1 inhibition of the TORC1 and TORC2 networks that comprise TOR signalling. One hundred and thirty of these sites were regulated by both perturbations, and the majority of these (119) new targets have not previously been linked to either nutritional or TOR control in either yeasts or humans. Elimination of AMPK inhibition of TORC1, by removal of AMPKα (ssp2::ura4+), identified phosphosites where nitrogen stress-induced changes were independent of TOR control. Using a yeast strain with an ATP analogue-sensitized Cdc2 kinase, we excluded sites that were changed as an indirect consequence of mitotic control modulation by nitrogen stress or TOR signalling. Nutritional control of gene expression was reflected in multiple targets in RNA metabolism, while significant modulation of actin cytoskeletal components points to adaptations in morphogenesis and cell integrity networks. Reduced phosphorylation of the MAPKK Byr1, at a site whose human equivalent controls docking between MEK and ERK, prevented sexual differentiation when resources were sparse but not eliminated.
Keywords	TORC1 ; TORC2 ; nitrogen stress ; phosphoproteome ; fission yeast Schizosaccharomyces pombe ; Byr1 MAPKK ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	The Royal Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The RNA-Binding Protein Scp160p Facilitates Aggregation of Many Endogenous Q/N-Rich Proteins

Matthew H.K. Cheng / Patrick C. Hoffmann / Mirita Franz-Wachtel / Carola Sparn / Charlotte Seng / Boris Maček / Ralf-Peter Jansen

Cell Reports, Vol 24, Iss 1, Pp 20-

2018 Volume 26

Abstract: Summary: The RNA-binding protein Scp160p is the yeast homolog of the conserved vigilin protein family. These proteins influence a variety of nuclear and cytoplasmic functions. One of Scp160p’s reported roles is to increase translation elongation ... ...

Abstract	Summary: The RNA-binding protein Scp160p is the yeast homolog of the conserved vigilin protein family. These proteins influence a variety of nuclear and cytoplasmic functions. One of Scp160p’s reported roles is to increase translation elongation efficiency in a manner related to codon usage. Thus, it can affect translation speed and co-translational folding of nascent peptides. We used polyglutamine (polyQ) reporters to assess Scp160p’s effect on protein synthesis and observed that, in the absence of Scp160p, aggregation of polyQ is reduced and toxicity is abolished. We additionally took a proteomic approach and analyzed the impact of Scp160p on the aggregation of endogenous proteins under normal growth conditions. In the absence of Scp160p, aggregation of many Q/N-rich proteins was reduced. Because aggregation mediated by these regions can be important for the proteins’ functions, Scp160p may affect many processes via aggregation of Q/N-rich proteins. : Glutamine and asparagine (Q/N)-mediated protein aggregation can lead to neurodegenerative diseases but is also functionally important. Cheng et al. report a method to assess aggregation of proteins at the proteomic level and observe reduced aggregation of many endogenous Q/N-rich proteins in the absence of the yeast vigilin protein. Keywords: vigilin, polyglutamine, protein aggregation, codon usage, low complexity regions, SCP160
Keywords	Biology (General) ; QH301-705.5
Subject code	612
Language	English
Publishing date	2018-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The integral spliceosomal component CWC15 is required for development in Arabidopsis

Daniel Slane / Cameron H. Lee / Martina Kolb / Craig Dent / Yingjing Miao / Mirita Franz-Wachtel / Steffen Lau / Boris Maček / Sureshkumar Balasubramanian / Martin Bayer / Gerd Jürgens

Scientific Reports, Vol 10, Iss 1, Pp 1-

2020 Volume 13

Abstract: Abstract Efficient mRNA splicing is a prerequisite for protein biosynthesis and the eukaryotic splicing machinery is evolutionarily conserved among species of various phyla. At its catalytic core resides the activated splicing complex Bact consisting of ... ...

Abstract	Abstract Efficient mRNA splicing is a prerequisite for protein biosynthesis and the eukaryotic splicing machinery is evolutionarily conserved among species of various phyla. At its catalytic core resides the activated splicing complex Bact consisting of the three small nuclear ribonucleoprotein complexes (snRNPs) U2, U5 and U6 and the so-called NineTeen complex (NTC) which is important for spliceosomal activation. CWC15 is an integral part of the NTC in humans and it is associated with the NTC in other species. Here we show the ubiquitous expression and developmental importance of the Arabidopsis ortholog of yeast CWC15. CWC15 associates with core components of the Arabidopsis NTC and its loss leads to inefficient splicing. Consistent with the central role of CWC15 in RNA splicing, cwc15 mutants are embryo lethal and additionally display strong defects in the female haploid phase. Interestingly, the haploid male gametophyte or pollen in Arabidopsis, on the other hand, can cope without functional CWC15, suggesting that developing pollen might be more tolerant to CWC15-mediated defects in splicing than either embryo or female gametophyte.
Keywords	Medicine ; R ; Science ; Q
Subject code	580
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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