54 research outputs found

    Emerging Role of the Nucleolar Stress Response in Autophagy

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    Autophagy represents a conserved self-digestion program, which allows regulated degradation of cellular material. Autophagy is activated by cellular stress, serum starvation and nutrient deprivation. Several autophagic pathways have been uncovered, which either non-selectively or selectively target the cellular cargo for lysosomal degradation. Autophagy engages the coordinated action of various key regulators involved in the steps of autophagosome formation, cargo targeting and lysosomal fusion. While non-selective (macro)autophagy is required for removal of bulk material or recycling of nutrients, selective autophagy mediates specific targeting of damaged organelles or protein aggregates. By proper action of the autophagic machinery, cellular homeostasis is maintained. In contrast, failure of this fundamental process is accompanied by severe pathophysiological conditions. Hallmarks of neuropathological disorders are for instance accumulated, mis-folded protein aggregates and damaged mitochondria. The nucleolus has been recognized as central hub in the cellular stress response. It represents a sub-nuclear organelle essential for ribosome biogenesis and also functions as stress sensor by mediating cell cycle arrest or apoptosis. Thus, proper nucleolar function is mandatory for cell growth and survival. Here, I highlight the emerging role of nucleolar factors in the regulation of autophagy. Moreover, I discuss the nucleolar stress response as a novel signaling pathway in the context of autophagy, health and disease

    Lypd6 Enhances Wnt/β-Catenin Signaling by Promoting Lrp6 Phosphorylation in Raft Plasma Membrane Domains

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    Wnt/beta-catenin signaling plays critical roles during embryogenesis, tissue homeostasis, and regeneration. How Wnt-receptor complex activity is regulated is not yet fully understood. Here, we identify the Ly6 family protein LY6/PLAUR domain-containing 6 (Lypd6) as a positive feedback regulator of Wnt/beta-catenin signaling. lypd6 enhances Wnt signaling in zebrafish and Xenopus embryos and in mammalian cells, and it is required for wnt8-mediated patterning of the mesoderm and neuroectoderm during zebrafish gastrulation. Lypd6 is GPI anchored to the plasma membrane and physically interacts with the Wnt receptor Frizzled8 and the coreceptor Lrp6. Biophysical and biochemical evidence indicates that Lypd6 preferentially localizes to raft membrane domains, where Lrp6 is phosphorylated upon Wnt stimulation. lypd6 knockdown or mislocalization of the Lypd6 protein to nonraft membrane domains shifts Lrp6 phosphorylation to these domains and inhibits Wnt signaling. Thus, Lypd6 appears to control Lrp6 activation specifically in membrane rafts, which is essential for downstream signaling.The GenBank accession number for the partial Xenopus laevis lypd6 complementary DNA reported in this paper is KF042353

    EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

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    More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369

    26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

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    This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

    An Update on Nucleolar Stress: The Transcriptional Control of Autophagy

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    Nucleolar stress reflects a misfunction of the nucleolus caused by a failure in ribosome biogenesis and defective nucleolar architecture. Various causes have been reported, most commonly mutation of ribosomal proteins and ribosome processing factors, as well as interference with these processes by intracellular or ectopic stress, such as RNA polymerase I inhibition, ROS, UV and others. The nucleolus represents the place for ribosome biogenesis and serves as a crucial hub in the cellular stress response. It has been shown to stimulate multiple downstream consequences, interfering with cell growth and survival. Nucleolar stress induction is most classically known to stimulate p53-dependent cell cycle arrest and apoptosis. Nucleolar stress represents a friend and enemy at the same time: From a pathophysiological perspective, inactivation of the nucleolar function by mutation or stress conditions is connected to multiple diseases, such as neurodegeneration, cancer and ribosomopathy syndromes. However, triggering the nucleolar stress response via specific chemotherapeutics, which interfere with nucleolar function, has beneficial effects for anti-cancer therapy. Interestingly, since the nucleolar stress response also triggers p53-independent mechanisms, it possesses the potential to specifically target p53-mutated tumors, which reflects the most common aberration in human cancer. More recent data have shown that the nucleolar stress response can activate autophagy and diverse signaling cascades that might allow initial pro-survival mechanisms. Nevertheless, it depends on the situation whether the cells undergo autophagy-mediated apoptosis or survive, as seen for autophagy-dependent drug resistance of chemotherapy-exposed tumor cells. Given the relatively young age of the research field, precise mechanisms that underly the involvement of autophagy in nucleolar stress are still under investigation. This review gives an update on the emerging contribution of nucleolar stress in the regulation of autophagy at a transcriptional level. It also appears that in autophagy p53-dependent as well as -independent responses are induced. Those could be exploited in future therapies against diseases connected to nucleolar stress

    Nucleolar Stress Functions Upstream to Stimulate Expression of Autophagy Regulators

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    Ribosome biogenesis is essential for protein synthesis, cell growth and survival. The process takes places in nucleoli and is orchestrated by various proteins, among them RNA polymerases I–III as well as ribosome biogenesis factors. Perturbation of ribosome biogenesis activates the nucleolar stress response, which classically triggers cell cycle arrest and apoptosis. Nucleolar stress is utilized in modern anti-cancer therapies, however, also contributes to the development of various pathologies, including cancer. Growing evidence suggests that nucleolar stress stimulates compensatory cascades, for instance bulk autophagy. However, underlying mechanisms are poorly understood. Here we demonstrate that induction of nucleolar stress activates expression of key autophagic regulators such as ATG7 and ATG16L1, essential for generation of autophagosomes. We show that knockdown of the ribosomopathy factor SBDS, or of key ribosome biogenesis factors (PPAN, NPM, PES1) is associated with enhanced levels of ATG7 in cancer cells. The same holds true when interfering with RNA polymerase I function by either pharmacological inhibition (CX-5461) or depletion of the transcription factor UBF-1. Moreover, we demonstrate that RNA pol I inhibition by CX-5461 stimulates autophagic flux. Together, our data establish that nucleolar stress affects transcriptional regulation of autophagy. Given the contribution of both axes in propagation or cure of cancer, our data uncover a connection that might be targeted in future

    Comparative Analysis Reveals Distinct and Overlapping Functions of Mef2c and Mef2d during Cardiogenesis in <i>Xenopus laevis</i>

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    <div><p>The family of vertebrate Mef2 transcription factors is comprised of four members named Mef2a, Mef2b, Mef2c, and Mef2d. These transcription factors are regulators of the myogenic programs with crucial roles in development of skeletal, cardiac and smooth muscle cells. Mef2a and Mef2c are essential for cardiac development in mice. In <i>Xenopus</i>, <i>mef2c</i> and <i>mef2d</i> but not <i>mef2a</i> were recently shown to be expressed during cardiogenesis. We here investigated the function of Mef2c and Mef2d during <i>Xenopus laevis</i> cardiogenesis. Knocking down either gene by corresponding antisense morpholino oligonucleotides led to profound heart defects including morphological abnormalities, pericardial edema, and brachycardia. Marker gene expression analyses and rescue experiments revealed that (i) both genes are required for proper cardiac gene expression, (ii) Mef2d can compensate for the loss of Mef2c but not <i>vice versa</i>, and (iii) the γ domain of Mef2c is required for early cardiac development. Taken together, our data provide novel insights into the function of Mef2 during cardiogenesis, highlight evolutionary differences between species and might have an impact on attempts of direct reprogramming.</p></div

    Cooperation of Mef2c and Mef2d in <i>Xenopus</i>.

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    <p><b>A, B.</b> The injection of 7(in both cases 3.5 ng per blastomere) did not result in cardiac defects. The co-injection of 7 ng Mef2c together with 7 ng Mef2d MO led to a significant increase of the phenotype. The dotted black lines indicate the heart. <b>C, D.</b> Mef2c MO was unilaterally injected along with RNA coding for hMEF2D. Expression of cardiac marker genes was monitored at stages 20 (<i>tbx20</i>, <i>bmp4</i>; anterior views) or stage 28 (<i>myh6</i>, <i>tnni3</i>; ventral views), respectively. <b>E, F.</b> Mef2d MO was unilaterally injected along with <i>mMef2c</i>γ+ RNA. Expression of cardiac marker genes was monitored at stages 20 (<i>tbx1</i>, <i>tbx20</i>; anterior views) or stage 28 (<i>bmp4</i>, <i>myh6</i>, <i>tnni3</i>; ventral views), respectively. <b>G, H.</b> Mef2d MO was unilaterally injected along with <i>mMef2c</i>γ ˜ RNA. Expression of cardiac marker genes was monitored at stage 28 (ventral view). In all cases, black arrowheads indicate reduced marker gene expression, white arrowheads highlight the rescued expression. <b>B, D, F, H.</b> Quantitative presentations of the experiments shown in <b>C, E, G</b> are shown. N: number of examined embryos; n: number of independent experiments; *, <i>p</i>≤0.05; **, <i>p</i>≤0.01.</p
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