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26 Publications visible to you, out of a total of 26
Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability.

Abstract (Expand)

Rationale: Arterial inflammation manifested as atherosclerosis is the leading cause of mortality worldwide. Genome-wide association studies have identified a prominent role of HDAC (histone deacetylase)-9 … in atherosclerosis and its clinical complications including stroke and myocardial infarction. Objective: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection. Methods and Results: We studied the effects of Hdac9 on features of plaque vulnerability using bone marrow reconstitution experiments and pharmacological targeting with a small molecule inhibitor in hyperlipidemic mice. We further used 2-photon and intravital microscopy to study endothelial activation and leukocyte-endothelial interactions. We show that hematopoietic Hdac9 deficiency reduces lesional macrophage content while increasing fibrous cap thickness thus conferring plaque stability. We demonstrate that HDAC9 binds to IKK (inhibitory kappa B kinase)-α and β, resulting in their deacetylation and subsequent activation, which drives inflammatory responses in both macrophages and endothelial cells. Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting proinflammatory responses in macrophages. Transcriptional profiling using RNA sequencing revealed that TMP195 downregulates key inflammatory pathways consistent with inhibitory effects on IKKβ. TMP195 mitigates the progression of established lesions and inhibits the infiltration of inflammatory cells. Moreover, TMP195 diminishes features of plaque vulnerability and thereby enhances plaque stability in advanced lesions. Ex vivo treatment of monocytes from patients with established atherosclerosis reduced the production of inflammatory cytokines including IL (interleukin)-1β and IL-6. Conclusions: Our findings identify HDAC9 as a regulator of atherosclerotic plaque stability and IKK activation thus providing a mechanistic explanation for the prominence of HDAC9 as a vascular risk locus in genome-wide association studies. Its therapeutic inhibition may provide a potent lever to alleviate vascular inflammation.

Authors: Yaw Asare, Thomas A Campbell-James, Yury Bokov, Lydia Luya Yu, Matthias Prestel, Omar El Bounkari, Stefan Roth, Remco T A Megens, Tobias Straub, Kyra Thomas, Guangyao Yan, Melanie Schneider, Natalie Ziesch, Steffen Tiedt, Carlos Silvestre-Roig, Quinte Braster, Yishu Huang, Manuela Schneider, Rainer Malik, Christof Haffner, Arthur Liesz, Oliver Soehnlein, Jürgen Bernhagen, Martin Dichgans

Date Published: 28th Aug 2020

Publication Type: Journal

Trnp1 organizes diverse nuclear membrane-less compartments in neural stem cells.

Abstract (Expand)

TMF1-regulated nuclear protein 1 (Trnp1) has been shown to exert potent roles in neural development affecting neural stem cell self-renewal and brain folding, but its molecular function in the nucleus … is still unknown. Here, we show that Trnp1 is a low complexity protein with the capacity to phase separate. Trnp1 interacts with factors located in several nuclear membrane-less organelles, the nucleolus, nuclear speckles, and condensed chromatin. Importantly, Trnp1 co-regulates the architecture and function of these nuclear compartments in vitro and in the developing brain in vivo. Deletion of a highly conserved region in the N-terminal intrinsic disordered region abolishes the capacity of Trnp1 to regulate nucleoli and heterochromatin size, proliferation, and M-phase length; decreases the capacity to phase separate; and abrogates most of Trnp1 protein interactions. Thus, we identified Trnp1 as a novel regulator of several nuclear membrane-less compartments, a function important to maintain cells in a self-renewing proliferative state.

Authors: Miriam Esgleas, Sven Falk, Ignasi Forné, Marc Thiry, Sonia Najas, Sirui Zhang, Aina Mas-Sanchez, Arie Geerlof, Dierk Niessing, Zefeng Wang, Axel Imhof, Magdalena Götz

Date Published: 17th Aug 2020

Publication Type: Journal

Filling the Gaps - A Call for Comprehensive Analysis of Extracellular Matrix of the Glial Scar in Region- and Injury-Specific Contexts.

Abstract (Expand)

Central nervous system (CNS) injury results in chronic scar formation that interferes with function and inhibits repair. Extracellular matrix (ECM) is prominent in the scar and potently regulates cell … behavior. However, comprehensive information about the ECM proteome is largely lacking, and region- as well as injury-specific differences are often not taken into account. These aspects are the focus of our perspective on injury and scar formation. To highlight the importance of such comprehensive proteome analysis we include data obtained with novel analysis tools of the ECM composition in the scar and show the contribution of monocytes to the ECM composition after traumatic brain injury (TBI). Monocyte invasion was reduced using the CCR2-/- mouse line and step-wise de-cellularization and proteomics allowed determining monocyte-dependent ECM composition and architecture of the glial scar. We find significant reduction in the ECM proteins Tgm1, Itih (1,2, and 3), and Ftl in the absence of monocyte invasion. We also describe the scar ECM comprising zones with distinctive composition and show a subacute signature upon comparison to proteome obtained at earlier times after TBI. These results are discussed in light of injury-, region- and time-specific regulation of scar formation highlighting the urgent need to differentiate injury conditions and CNS-regions using comprehensive ECM analysis.

Authors: Jacob Kjell, Magdalena Götz

Date Published: 20th Feb 2020

Publication Type: Journal

Defining the Adult Neural Stem Cell Niche Proteome Identifies Key Regulators of Adult Neurogenesis.

Abstract (Expand)

The mammalian brain contains few niches for neural stem cells (NSCs) capable of generating new neurons, whereas other regions are primarily gliogenic. Here we leverage the spatial separation of the … sub-ependymal zone NSC niche and the olfactory bulb, the region to which newly generated neurons from the sub-ependymal zone migrate and integrate, and present a comprehensive proteomic characterization of these regions in comparison to the cerebral cortex, which is not conducive to neurogenesis and integration of new neurons. We find differing compositions of regulatory extracellular matrix (ECM) components in the neurogenic niche. We further show that quiescent NSCs are the main source of their local ECM, including the multi-functional enzyme transglutaminase 2, which we show is crucial for neurogenesis. Atomic force microscopy corroborated indications from the proteomic analyses that neurogenic niches are significantly stiffer than non-neurogenic parenchyma. Together these findings provide a powerful resource for unraveling unique compositions of neurogenic niches.

Authors: Jacob Kjell, Judith Fischer-Sternjak, Amelia J Thompson, Christian Friess, Matthew J Sticco, Favio Salinas, Jürgen Cox, David C Martinelli, Jovica Ninkovic, Kristian Franze, Herbert B Schiller, Magdalena Götz

Date Published: 6th Feb 2020

Publication Type: Journal

The ubiquitin-conjugating enzyme UBE2QL1 coordinates lysophagy in response to endolysosomal damage.

Abstract (Expand)

The autophagic clearance of damaged lysosomes by lysophagy involves extensive modification of the organelle with ubiquitin, but the underlying ubiquitination machinery is still poorly characterized. … Here, we use an siRNA screening approach and identify human UBE2QL1 as a major regulator of lysosomal ubiquitination, lysophagy, and cell survival after lysosomal damage. UBE2QL1 translocates to permeabilized lysosomes where it associates with damage sensors, ubiquitination targets, and lysophagy effectors. UBE2QL1 knockdown reduces ubiquitination and accumulation of the critical autophagy receptor p62 and abrogates recruitment of the AAA-ATPase VCP/p97, which is essential for efficient lysophagy. Crucially, it affects association of LC3B with damaged lysosomes indicating that autophagosome formation was impaired. Already in unchallenged cells, depletion of UBE2QL1 leads to increased lysosomal damage, mTOR dissociation from lysosomes, and TFEB activation pointing to a role in lysosomal homeostasis. In line with this, mutation of the homologue ubc-25 in Caenorhabditis elegans exacerbates lysosome permeability in worms lacking the lysosome stabilizing protein SCAV-3/LIMP2. Thus, UBE2QL1 coordinates critical steps in the acute endolysosomal damage response and is essential for maintenance of lysosomal integrity.

Authors: Lisa Koerver, Chrisovalantis Papadopoulos, Bin Liu, Bojana Kravic, Giulia Rota, Lukas Brecht, Tineke Veenendaal, Mira Polajnar, Anika Bluemke, Michael Ehrmann, Judith Klumperman, Marja Jäättelä, Christian Behrends, Hemmo Meyer

Date Published: 4th Oct 2019

Publication Type: Journal

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