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Diaz-Munoz M.D.,Babraham Institute | Bell S.E.,Babraham Institute | Fairfax K.,Babraham Institute | Fairfax K.,Walter and Eliza Hall Institute of Medical Research | And 15 more authors.
Nature Immunology | Year: 2015

Post-transcriptional regulation of mRNA by the RNA-binding protein HuR (encoded by Elavl1) is required in B cells for the germinal center reaction and for the production of class-switched antibodies in response to thymus-independent antigens. Transcriptome-wide examination of RNA isoforms and their abundance and translation in HuR-deficient B cells, together with direct measurements of HuR-RNA interactions, revealed that HuR-dependent splicing of mRNA affected hundreds of transcripts, including that encoding dihydrolipoamide S-succinyltransferase (Dlst), a subunit of the 2-oxoglutarate dehydrogenase (α-KGDH) complex. In the absence of HuR, defective mitochondrial metabolism resulted in large amounts of reactive oxygen species and B cell death. Our study shows how post-transcriptional processes control the balance of energy metabolism required for the proliferation and differentiation of B cells. © 2015 Nature America, Inc. All rights reserved.


Figge M.T.,Leibniz Institute for Natural Product Research and Infection Biology | Figge M.T.,Frankfurt Institute for Advanced Studies | Figge M.T.,Helmholtz Center for Infection Research | Reichert A.S.,Goethe University Frankfurt | And 4 more authors.
PLoS Computational Biology | Year: 2012

Mitochondrial dynamics and mitophagy play a key role in ensuring mitochondrial quality control. Impairment thereof was proposed to be causative to neurodegenerative diseases, diabetes, and cancer. Accumulation of mitochondrial dysfunction was further linked to aging. Here we applied a probabilistic modeling approach integrating our current knowledge on mitochondrial biology allowing us to simulate mitochondrial function and quality control during aging in silico. We demonstrate that cycles of fusion and fission and mitophagy indeed are essential for ensuring a high average quality of mitochondria, even under conditions in which random molecular damage is present. Prompted by earlier observations that mitochondrial fission itself can cause a partial drop in mitochondrial membrane potential, we tested the consequences of mitochondrial dynamics being harmful on its own. Next to directly impairing mitochondrial function, pre-existing molecular damage may be propagated and enhanced across the mitochondrial population by content mixing. In this situation, such an infection-like phenomenon impairs mitochondrial quality control progressively. However, when imposing an age-dependent deceleration of cycles of fusion and fission, we observe a delay in the loss of average quality of mitochondria. This provides a rational why fusion and fission rates are reduced during aging and why loss of a mitochondrial fission factor can extend life span in fungi. We propose the 'mitochondrial infectious damage adaptation' (MIDA) model according to which a deceleration of fusion-fission cycles reflects a systemic adaptation increasing life span. © 2012 Figge et al.


Sampaio-Marques B.,University of Minho | Sampaio-Marques B.,ICVS 3Bs PT Government Associate Laboratory | Felgueiras C.,University of Minho | Felgueiras C.,ICVS 3Bs PT Government Associate Laboratory | And 13 more authors.
Autophagy | Year: 2012

SNCA (α-synuclein) misfolding and aggregation is strongly associated with both idiopathic and familial forms of Parkinson disease (PD). Evidence suggests that SNCA has an impact on cell clearance routes and protein quality control systems such as the ubiquitin-proteasome system (UPS) and autophagy. Recent advances in the key role of the autosomal recessive PARK2/PARKIN and PINK1 genes in mitophagy, highlighted this process as a prominent new pathogenic mechanism. Nevertheless, the role of autophagy/mitophagy in the pathogenesis of sporadic and autosomal dominant familial forms of PD is still enigmatic. The yeast Saccharomyces cerevisiae is a powerful "empty room" model that has been exploited to clarify different molecular aspects associated with SNCA toxicity, which combines the advantage of being an established system for aging research. The contribution of autophagy/mitophagy for the toxicity induced by the heterologous expression of the human wild-type SNCA gene and the clinical A53T mutant during yeast chronological life span (CLS) was explored. A reduced CLS together with an increase of autophagy and mitophagy activities were observed in cells expressing both forms of SNCA. Impairment of mitophagy by deletion of ATG11 or ATG32 resulted in a CLS extension, further implicating mitophagy in the SNCA toxicity. Deletion of SIR2, essential for SNCA toxicity, abolished autophagy and mitophagy, thereby rescuing cells. These data show that Sir2 functions as a regulator of autophagy, like its mammalian homolog, SIRT1, but also of mitophagy. Our work highlights that increased mitophagy activity, mediated by the regulation of ATG32 by Sir2, is an important phenomenon linked to SNCA-induced toxicity during aging. © 2012 Landes Bioscience.


Geiss C.P.,Buchmann Institute for Molecular Life science | Keramisanou D.,Buchmann Institute for Molecular Life science | Sekulic N.,University of Pennsylvania | Scheffer M.P.,Buchmann Institute for Molecular Life science | And 2 more authors.
Biophysical Journal | Year: 2014

Summary The centromeric histone H3 variant centromeric protein A (CENP-A), whose sequence is the least conserved among all histone variants, is responsible for specifying the location of the centromere. Here, we present a comprehensive study of CENP-A nucleosome arrays by cryo-electron tomography. We see that CENP-A arrays have different biophysical properties than canonical ones under low ionic conditions, as they are more condensed with a 20% smaller average nearest-neighbor distance and a 30% higher nucleosome density. We find that CENP-A nucleosomes have a predominantly crossed DNA entry/exit site that is narrowed on average by 8, and they have a propensity to stack face to face. We therefore propose that CENP-A induces geometric constraints at the nucleosome DNA entry/exit site to bring neighboring nucleosomes into close proximity. This specific property of CENP-A may be responsible for generating a fundamental process that contributes to increased chromatin fiber compaction that is propagated under physiological conditions to form centromeric chromatin. © 2014 Biophysical Society.


Frank M.,Ludwig Maximilians University of Munich | Duvezin-Caubet S.,Ludwig Maximilians University of Munich | Duvezin-Caubet S.,French National Center for Scientific Research | Duvezin-Caubet S.,University of Bordeaux 1 | And 13 more authors.
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2012

Mitochondrial dysfunction is linked to apoptosis, aging, cancer, and a number of neurodegenerative and muscular disorders. The interplay between mitophagy and mitochondrial dynamics has been linked to the removal of dysfunctional mitochondria ensuring mitochondrial quality control. An open question is what role mitochondrial fission plays in the removal of mitochondria after mild and transient oxidative stress; conditions reported to result in moderately elevated reactive oxygen species (ROS) levels comparable to physical activity. Here we show that applying such conditions led to fragmentation of mitochondria and induction of mitophagy in mouse and human cells. These conditions increased ROS levels only slightly and neither triggered cell death nor led to a detectable induction of non-selective autophagy. Starvation led to hyperfusion of mitochondria, to high ROS levels, and to the induction of both non-selective autophagy and to a lesser extent to mitophagy. We conclude that moderate levels of ROS specifically trigger mitophagy but are insufficient to trigger non-selective autophagy. Expression of a dominant-negative variant of the fission factor DRP1 blocked mitophagy induction by mild oxidative stress as well as by starvation. Taken together, we demonstrate that in mammalian cells under mild oxidative stress a DRP1-dependent type of mitophagy is triggered while a concomitant induction of non-selective autophagy was not observed. We propose that these mild oxidative conditions resembling well physiological situations are thus very helpful for studying the molecular pathways governing the selective removal of dysfunctional mitochondria. © 2012 Elsevier B.V.


Khaminets A.,Goethe University Frankfurt | Khaminets A.,Buchmann Institute for Molecular Life science | Behl C.,Johannes Gutenberg University Mainz | Dikic I.,Goethe University Frankfurt | Dikic I.,Buchmann Institute for Molecular Life science
Trends in Cell Biology | Year: 2016

Selective autophagy regulates the abundance of specific cellular components via a specialized arsenal of factors, termed autophagy receptors, that target protein complexes, aggregates, and whole organelles into lysosomes. Autophagy receptors bind to LC3/GABARAP proteins on phagophore and autophagosome membranes, and recognize signals on cargoes to deliver them to autophagy. Ubiquitin (Ub), a well-known signal for the degradation of polypeptides in the proteasome, also plays an important role in the recognition of cargoes destined for selective autophagy. In addition, a variety of cargoes are committed to selective autophagy pathways by Ub-independent mechanisms employing protein-protein interaction motifs, Ub-like modifiers, and sugar- or lipid-based signals. In this article we summarize Ub-dependent and independent selective autophagy pathways, and discuss regulatory mechanisms and challenges for future studies. Ubiquitin is a universal degradation signal used for protein disposal via proteasome and autophagy.Selective autophagy pathways are regulated by phosphorylation and ubiquitination.In contrast to core autophagy machinery, autophagy receptors are divergent and poorly conserved from yeast to humans; however, functional homologs are present.Autophagy receptors target damaged or foreign cytosolic material by recognizing specific protein, sugar, or lipid moieties.Autophagy receptors act together with autophagy adaptors in recognizing and processing cargo via selective autophagy. © 2015 Elsevier Ltd.


Brieke C.,Goethe University Frankfurt | Rohrbach F.,University of Bonn | Gottschalk A.,Buchmann Institute for Molecular Life science | Mayer G.,University of Bonn | Heckel A.,Goethe University Frankfurt
Angewandte Chemie - International Edition | Year: 2012

Spatial and temporal control over chemical and biological processes plays a key role in life, where the whole is often much more than the sum of its parts. Quite trivially, the molecules of a cell do not form a living system if they are only arranged in a random fashion. If we want to understand these relationships and especially the problems arising from malfunction, tools are necessary that allow us to design sophisticated experiments that address these questions. Highly valuable in this respect are external triggers that enable us to precisely determine where, when, and to what extent a process is started or stopped. Light is an ideal external trigger: It is highly selective and if applied correctly also harmless. It can be generated and manipulated with well-established techniques, and many ways exist to apply light to living systems-from cells to higher organisms. This Review will focus on developments over the last six years and includes discussions on the underlying technologies as well as their applications. Spot on! Systems which can be regulated by using light as a trigger can be used for very sophisticated experiments in which aspects of space, time, or extent of activation are to be studied. Irreversible photocleavage, reversible photoswitching, and genetically expressible systems are the three possibilities for coupling the trigger to an effect. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Stolz A.,Goethe University Frankfurt | Dikic I.,Goethe University Frankfurt | Dikic I.,Buchmann Institute for Molecular Life science
Molecular Cell | Year: 2014

By using quantitative proteomics, Ordureau etal. (2014) provide a comprehensive view on the regulatory steps by which PINK1-mediated phosphorylation of PARKIN and ubiquitin triggers the recruitment of the ubiquitin ligase PARKIN to damaged mitochondria. © 2014 Elsevier Inc.


Stolz A.,Goethe University Frankfurt | Ernst A.,Goethe University Frankfurt | Dikic I.,Goethe University Frankfurt | Dikic I.,Buchmann Institute for Molecular Life science
Nature Cell Biology | Year: 2014

Selective autophagy is a quality control pathway through which cellular components are sequestered into double-membrane vesicles and delivered to specific intracellular compartments. This process requires autophagy receptors that link cargo to growing autophagosomal membranes. Selective autophagy is also implicated in various membrane trafficking events. Here we discuss the current view on how cargo selection and transport are achieved during selective autophagy, and point out molecular mechanisms that are congruent between autophagy and vesicle trafficking pathways. © 2014 Macmillan Publishers Limited. All rights reserved.


PubMed | Goethe University Frankfurt and Buchmann Institute for Molecular Life science
Type: Journal Article | Journal: Cell research | Year: 2016

Eukaryotic cells utilize the ubiquitin (Ub) system for maintaining a balanced functioning of cellular pathways. Although the Ub system is exclusive to eukaryotes, prokaryotic bacteria have developed an armory of Ub ligase enzymes that are capable of employing the Ub systems of various hosts, ranging from plant to animal cells. These enzymes have been acquired through the evolution and can be classified into three main classes, RING (really interesting new gene), HECT (homologous to the E6-AP carboxyl terminus) and NEL (novel E3 ligases). In this review we describe the roles played by different classes of bacterial Ub ligases in infection and pathogenicity. We also provide an overview of the different mechanisms by which bacteria mimic specific components of the host Ub system and outline the gaps in our current understanding of their functions. Additionally, we discuss approaches and experimental tools for validating this class of enzymes as potential novel antibacterial therapy targets.

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