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News Article | April 21, 2017
Site: www.eurekalert.org

Early in evolution, sugar intake and the regulation of life span were linked with each other. The hormone insulin is crucial here. It reduces blood sugar levels by binding to its receptor on the cell surface. However, many processes for stress management and survival are shut down at the same time. When there is a good supply of food, they appear unnecessary to the organism, although this reduces life expectancy over the long term. The insulin receptor thus acts like a brake on life expectancy. Genetically altered laboratory animals in which the insulin receptor no longer functions actually live much longer than normal. But how is the insulin receptor normally kept in check in our cells and tissue? A recent study by scientists at the Universities of Cologne and Bonn answers this fundamental question. The team of researchers shows that the protein CHIP plays a crucial role here. It acts like a disposal helper, in that it supplies the insulin receptor to the cellular breakdown and recycling systems by affixing a "green dot" in the form of the molecule ubiquitin onto the receptor. The life expectancy brake is thus released and CHIP unfurls anti-aging activity. "CHIP fulfils this function in nematodes, as well as in fruit flies and in humans. This makes the protein so interesting for us," explains Prof. Thorsten Hoppe, one of the two lead authors of the study from the Cluster of Excellence CECAD at the University of Cologne. When CHIP is missing, it leads to premature aging The findings were initially very surprising, as CHIP had so far been associated with completely different breakdown processes. Specifically, CHIP also disposes of faulty and damaged proteins, which increasingly occur at an older age and the accumulation of which leads to dementia and muscle weakness. The researchers actually recreated such degenerative illnesses in the nematode and in human cells and observed that there was no longer enough CHIP available to break down the insulin receptor. Premature aging is the result. Can the dream of a fountain of youth be made a reality and life extended in that researchers encourage cells to form more CHIP? "Unfortunately, it's not that easy," says lead author Prof. Jörg Höhfeld from the Institute for Cell Biology at the University of Bonn. When there is too much CHIP, undamaged proteins are also recycled and the organism is weakened. However, the researchers are already looking for mechanisms that control CHIP when breaking down the insulin receptor and that could one day also be used for new treatments. Publication: The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover, "Cell", DOI: 10.1016/j.cell.2017.04.003 Prof. Thorsten Hoppe CECAD Cologne and Institute for Genetics University of Cologne Tel. +49 221/47884218 E-mail: thorsten.hoppe@uni-koeln.de


News Article | April 25, 2017
Site: www.medicalnewstoday.com

Not only does our way of life determine how long we live but so too does our genetic material. Of particular importance here is a genetic program that is controlled by the insulin receptor. A team of researchers from the Universities of Cologne and Bonn has now discovered how protein aggregation affects this genetic program and thus triggers aging. The results have now been published in the journal Cell. Early in evolution, sugar intake and the regulation of life span were linked with each other. The hormone insulin is crucial here. It reduces blood sugar levels by binding to its receptor on the cell surface. However, many processes for stress management and survival are shut down at the same time. When there is a good supply of food, they appear unnecessary to the organism, although this reduces life expectancy over the long term. The insulin receptor thus acts like a brake on life expectancy. Genetically altered laboratory animals in which the insulin receptor no longer functions actually live much longer than normal. But how is the insulin receptor normally kept in check in our cells and tissue? A recent study by scientists at the Universities of Cologne and Bonn answers this fundamental question. The team of researchers shows that the protein CHIP plays a crucial role here. It acts like a disposal helper, in that it supplies the insulin receptor to the cellular breakdown and recycling systems by affixing a "green dot" in the form of the molecule ubiquitin onto the receptor. The life expectancy brake is thus released and CHIP unfurls anti-aging activity. "CHIP fulfils this function in nematodes, as well as in fruit flies and in humans. This makes the protein so interesting for us," explains Prof. Thorsten Hoppe, one of the two lead authors of the study from the Cluster of Excellence CECAD at the University of Cologne. The findings were initially very surprising, as CHIP had so far been associated with completely different breakdown processes. Specifically, CHIP also disposes of faulty and damaged proteins, which increasingly occur at an older age and the accumulation of which leads to dementia and muscle weakness. The researchers actually recreated such degenerative illnesses in the nematode and in human cells and observed that there was no longer enough CHIP available to break down the insulin receptor. Premature aging is the result. Can the dream of a fountain of youth be made a reality and life extended in that researchers encourage cells to form more CHIP? "Unfortunately, it's not that easy," says lead author Prof. Jörg Höhfeld from the Institute for Cell Biology at the University of Bonn. When there is too much CHIP, undamaged proteins are also recycled and the organism is weakened. However, the researchers are already looking for mechanisms that control CHIP when breaking down the insulin receptor and that could one day also be used for new treatments. Article: The Ubiquitin Ligase CHIP Integrates Proteostasis and Aging by Regulation of Insulin Receptor Turnover, Thorsten Hoppe et al., Cell, doi: 10.1016/j.cell.2017.04.003, published 20 April 2017.


Gerl M.J.,University of Heidelberg | Gerl M.J.,Lipotype GmbH | Bittl V.,University of Heidelberg | Kirchner S.,University of Heidelberg | And 11 more authors.
PLoS ONE | Year: 2016

Cell membranes contain hundreds to thousands of individual lipid species that are of structural importance but also specifically interact with proteins. Due to their highly controlled synthesis and role in signaling events sphingolipids are an intensely studied class of lipids. In order to investigate their metabolism and to study proteins interacting with sphingolipids, metabolic labeling based on photoactivatable sphingoid bases is the most straightforward approach. In order to monitor protein-lipid-crosslink products, sphingosine derivatives containing a reporter moiety, such as a radiolabel or a clickable group, are used. In normal cells, degradation of sphingoid bases via action of the checkpoint enzyme sphingosine-1-phosphate lyase occurs at position C2-C3 of the sphingoid base and channels the resulting hexadecenal into the glycerolipid biosynthesis pathway. In case the functionalized sphingosine looses the reporter moiety during its degradation, specificity towards sphingolipid labeling is maintained. In case degradation of a sphingosine derivative does not remove either the photoactivatable or reporter group from the resulting hexadecenal, specificity towards sphingolipid labeling can be achieved by blocking sphingosine-1-phosphate lyase activity and thus preventing sphingosine derivatives to be channeled into the sphingolipid-to-glycerolipid metabolic pathway. Here we report an approach using clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated nuclease Cas9 to create a sphingosine-1-phosphate lyase (SGPL1) HeLa knockout cell line to disrupt the sphingolipidto-glycerolipid metabolic pathway. We found that the lipid and protein compositions as well as sphingolipid metabolism of SGPL1 knock-out HeLa cells only show little adaptations, which validates these cells as model systems to study transient protein-sphingolipid interactions. © 2016 Gerl et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


PubMed | European Molecular Biology Laboratory, University of Heidelberg and CECAD
Type: Journal Article | Journal: PloS one | Year: 2016

Cell membranes contain hundreds to thousands of individual lipid species that are of structural importance but also specifically interact with proteins. Due to their highly controlled synthesis and role in signaling events sphingolipids are an intensely studied class of lipids. In order to investigate their metabolism and to study proteins interacting with sphingolipids, metabolic labeling based on photoactivatable sphingoid bases is the most straightforward approach. In order to monitor protein-lipid-crosslink products, sphingosine derivatives containing a reporter moiety, such as a radiolabel or a clickable group, are used. In normal cells, degradation of sphingoid bases via action of the checkpoint enzyme sphingosine-1-phosphate lyase occurs at position C2-C3 of the sphingoid base and channels the resulting hexadecenal into the glycerolipid biosynthesis pathway. In case the functionalized sphingosine looses the reporter moiety during its degradation, specificity towards sphingolipid labeling is maintained. In case degradation of a sphingosine derivative does not remove either the photoactivatable or reporter group from the resulting hexadecenal, specificity towards sphingolipid labeling can be achieved by blocking sphingosine-1-phosphate lyase activity and thus preventing sphingosine derivatives to be channeled into the sphingolipid-to-glycerolipid metabolic pathway. Here we report an approach using clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated nuclease Cas9 to create a sphingosine-1-phosphate lyase (SGPL1) HeLa knockout cell line to disrupt the sphingolipid-to-glycerolipid metabolic pathway. We found that the lipid and protein compositions as well as sphingolipid metabolism of SGPL1 knock-out HeLa cells only show little adaptations, which validates these cells as model systems to study transient protein-sphingolipid interactions.


Eichhorst B.,University of Cologne | Cramer P.,CECAD | Hallek M.,University of Cologne
Seminars in Oncology | Year: 2016

Only chronic lymphocytic leukemia (CLL) patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. Prognostic risk factor profile and comorbidity burden are most relevant for the choice of treatment. For physically fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab remains the current standard therapy. For unfit patients, treatment with an anti-CD20 antibody (obinutuzumab or rituximab or ofatumumab) plus milder chemotherapy (chlorambucil) may be applied. Patients with a del(17p) or TP53 mutation should be treated with the kinase inhibitors ibrutinib or a combination of idelalisib and rituximab. Clinical trials over the next several years will determine, whether kinase inhibitors, other small molecules, immunotherapeutics, or combinations thereof will further improve outcomes for patients with CLL. © 2016 Elsevier Inc. All rights reserved.


Kondadi A.K.,University of Cologne | Wang S.,University of Cologne | Montagner S.,University of Cologne | Kladt N.,CECAD | And 8 more authors.
EMBO Journal | Year: 2014

The m-AAA protease subunit AFG3L2 is involved in degradation and processing of substrates in the inner mitochondrial membrane. Mutations in AFG3L2 are associated with spinocerebellar ataxia SCA28 in humans and impair axonal development and neuronal survival in mice. The loss of AFG3L2 causes fragmentation of the mitochondrial network. However, the pathogenic mechanism of neurodegeneration in the absence of AFG3L2 is still unclear. Here, we show that depletion of AFG3L2 leads to a specific defect of anterograde transport of mitochondria in murine cortical neurons. We observe similar transport deficiencies upon loss of AFG3L2 in OMA1-deficient neurons, indicating that they are not caused by OMA1-mediated degradation of the dynamin-like GTPase OPA1 and inhibition of mitochondrial fusion. Treatment of neurons with antioxidants, such as N-acetylcysteine or vitamin E, or decreasing tau levels in axons restored mitochondrial transport in AFG3L2-depleted neurons. Consistently, tau hyperphosphorylation and activation of ERK kinases are detected in mouse neurons postnatally deleted for Afg3l2. We propose that reactive oxygen species signaling leads to cytoskeletal modifications that impair mitochondrial transport in neurons lacking AFG3L2. Synopsis Lack of the m-AAA protease subunit AFG3L2 impairs anterograde axonal transport of mitochondria via a mechanism that involves ROS signaling and hyperphosphorylation of the microtubule- associated protein tau. Depletion of AFG3L2 in cortical neurons leads to a specific defect of anterograde axonal transport of mitochondria. The mitochondrial transport defect is independent from OMA1-dependent OPA1 processing. Anterograde axonal transport of mitochondria in AFG3L2-depleted neurons is rescued by reducing tau levels and by treatment with antioxidants. Deletion of Afg3l2 in cortical neurons activates ERK kinases and leads to tau hyperphosphorylation. Impaired axonal transport of mitochondria in the absence of AFG3L2 may explain how its mutation in spinocerebellar ataxia impair neuronal development and survival, and suggests possible therapeutic strategies based on counteracting ROS signaling. © 2014 The Authors.


Turpin S.M.,Max Planck Institute for Metabolism Research | Nicholls H.T.,Max Planck Institute for Metabolism Research | Willmes D.M.,Max Planck Institute for Metabolism Research | Mourier A.,CECAD | And 16 more authors.
Cell Metabolism | Year: 2014

Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C14:0 to C30:0 and are synthesized by six ceramide synthase enzymes (CerS1-6). It remains unresolved whether obesity-associated alterations of specific CerSs and their defined acyl-chain length ceramides contribute to the manifestation of metabolic diseases. Here we reveal that CERS6 mRNA expression and C16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Conversely, CerS6-deficient (CerS6Δ/Δ) mice exhibit reduced C16:0 ceramides and are protected from high-fat-diet-induced obesity and glucose intolerance. CerS6 deletion increases energy expenditure and improves glucose tolerance, not only in CerS6Δ/Δ mice, but also in brown adipose tissue- (CerS6ΔBAT) and liver-specific (CerS6ΔLIVER) CerS6 knockout mice. CerS6 deficiency increases lipid utilization in BAT and liver. These experiments highlight CerS6 inhibition as a specific approach for the treatment of obesity and type 2 diabetes mellitus, circumventing the side effects of global ceramide synthesis inhibition. © 2014 Elsevier Inc.


PubMed | University of Leipzig, Max Planck Institute for Biology of Ageing, University of Cologne, Ecole Polytechnique Federale de Lausanne and 2 more.
Type: Journal Article | Journal: Cell metabolism | Year: 2014

Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C14:0 to C30:0 and are synthesized by six ceramide synthase enzymes (CerS1-6). It remains unresolved whether obesity-associated alterations of specific CerSs and their defined acyl-chain length ceramides contribute to the manifestation of metabolic diseases. Here we reveal that CERS6 mRNA expression and C16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Conversely, CerS6-deficient (CerS6(/)) mice exhibit reduced C16:0 ceramides and are protected from high-fat-diet-induced obesity and glucose intolerance. CerS6 deletion increases energy expenditure and improves glucose tolerance, not only in CerS6(/) mice, but also in brown adipose tissue- (CerS6(BAT)) and liver-specific (CerS6(LIVER)) CerS6 knockout mice. CerS6 deficiency increases lipid utilization in BAT and liver. These experiments highlight CerS6 inhibition as a specific approach for the treatment of obesity and type 2 diabetes mellitus, circumventing the side effects of global ceramide synthesis inhibition.


News Article | November 8, 2016
Site: www.eurekalert.org

Cell death is an essential physiological process for all multicellular organisms. Throughout life, cells in many tissues die naturally and are replaced by new cells. A proper balance between the death and production of new cells is important for the maintenance of healthy tissue function and for regeneration after injury. Increased cell production coupled with reduced cell death can lead to tumor development. On the other hand, excessive cell death can cause tissue damage and disease. Normally our tissues are healthy, but some individuals develop inflammation and disease. "What causes inflammation?" asks Manolis Pasparakis, Professor at the Institute for Genetics of the University of Cologne, who is the senior author of the paper published on November 7th in Nature. "Can necroptosis be the trigger of inflammation in some cases and how is necroptosis regulated?" RIPK1 is a protein mainly known as an inducer of necroptosis. Researchers in the group of Manolis Pasparakis generated mice in which the RIPK1 gene was inactivated specifically in skin cells called keratinocytes. "We expected that the lack of RIPK1 would prevent necroptosis - but we observed the opposite. Keratinocytes in these mice died by necroptosis, causing skin inflammation. This was puzzling: How could the removal of RIPK1 cause necroptosis?" asked Snehlata Kumari, one of the three main authors of the paper. The researchers have now found an answer to this question: they discovered that RIPK1 inhibits another inducer of necroptosis, a protein called ZBP1. Genetic elimination of ZBP1 inhibited necroptosis and inflammation caused by RIPK1 deficiency. "ZBP1 was known as a sensor of DNA that contributes to immunity against some viruses, but so far it has not been implicated in inflammation," commented Chun Kim, who is also a main author of the study. The researchers asked how RIPK1 can inhibit ZBP1. To answer this question, they used CRISPR gene editing to modify three amino acids in the so called RHIM domain that allows RIPK1 to interact with other proteins regulating necroptosis. Mice expressing this mutant RIPK1 in all cells did not survive after birth. Moreover, the expression of mutated RIPK1 only in keratinocytes caused skin inflammation. Using a combination of genetic and biochemical experiments, the researchers could show that when the RHIM domain of RIPK1 was mutated, ZBP1 triggered necroptosis. This is what caused perinatal death, but also skin inflammation in adult mice. "This was a surprising result. These three amino acids of RIPK1 prevent ZBP1 from inducing necroptosis, and this is essential for mouse survival and the prevention of skin inflammation," said Juan Lin, one of the leading authors of the manuscript. "We made progress, but many pieces of the greater puzzle remain unclear," says Manolis Pasparakis. "ZBP1 has been known as a viral sensor, and now our results linked it to inflammation and disease. The triggers of chronic inflammation in humans are, in most cases, entirely unclear. Why does inflammation occur in a certain person at a certain moment? Bacterial and viral infections are discussed as possible triggers of chronic inflammation. In our work, we discovered the role of ZBP1 by experimentally altering RIPK1. Now we are wondering whether viruses or bacteria could activate ZBP1 to cause inflammation." The researchers are now working to put the next pieces of the puzzle in place and explore a possible link between ZBP1 and chronic inflammatory diseases in humans. Prof. Dr. Manolis Pasparakis Institute for Genetics and Cluster of Excellence CECAD Tel. +49 221 478 84351 pasparakis@uni-koeln.de

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