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Tiffany A Thibaudeau, Raymond T Anderson, David M Smith
Protein accumulation and aggregation with a concomitant loss of proteostasis often contribute to neurodegenerative diseases, and the ubiquitin-proteasome system plays a major role in protein degradation and proteostasis. Here, we show that three different proteins from Alzheimer's, Parkinson's, and Huntington's disease that misfold and oligomerize into a shared three-dimensional structure potently impair the proteasome. This study indicates that the shared conformation allows these oligomers to bind and inhibit the proteasome with low nanomolar affinity, impairing ubiquitin-dependent and ubiquitin-independent proteasome function in brain lysates...
March 15, 2018: Nature Communications
Julie A Reisz, Alexander S Barrett, Travis Nemkov, Kirk C Hansen, Angelo D'Alessandro
Proteins have been historically regarded as "nature's robots": Molecular machines that are essential to cellular/extracellular physical mechanical properties and catalyze key reactions for cell/system viability. However, these robots are kept in check by other protein-based machinery to preserve proteome integrity and stability. During aging, protein homeostasis is challenged by oxidation, decreased synthesis, and increasingly inefficient mechanisms responsible for repairing or degrading damaged proteins...
March 14, 2018: Expert Review of Proteomics
Martin Höhne, Christian K Frese, Florian Grahammer, Claudia Dafinger, Giuliano Ciarimboli, Linus Butt, Julia Binz, Matthias J Hackl, Mahdieh Rahmatollahi, Martin Kann, Simon Schneider, Mehmet M Altintas, Bernhard Schermer, Thomas Reinheckel, Heike Göbel, Jochen Reiser, Tobias B Huber, Rafael Kramann, Tamina Seeger-Nukpezah, Max C Liebau, Bodo B Beck, Thomas Benzing, Andreas Beyer, Markus M Rinschen
In diseases of many parenchymatous organs, heterogeneous deterioration of individual functional units determines the clinical prognosis. However, the molecular characterization at the level of such individual subunits remains a technological challenge that needs to be addressed in order to better understand pathological mechanisms. Proteinuric glomerular kidney diseases are frequent and assorted diseases affecting a fraction of glomeruli and their draining tubules to variable extents, and for which no specific treatment exists...
March 9, 2018: Kidney International
Zhi-Chuan Zhu, Ji-Wei Liu, Kui Li, Jing Zheng, Zhi-Qi Xiong
The nuclear import receptor karyopherin β1 (KPNB1) is involved in the nuclear import of most proteins and in the regulation of multiple mitotic events. Upregulation of KPNB1 has been observed in cancers including glioblastoma. Depletion of KPNB1 induces mitotic arrest and apoptosis in cancer cells, but the underlying mechanism is not clearly elucidated. Here, we found that downregulation and functional inhibition of KPNB1 in glioblastoma cells induced growth arrest and apoptosis without apparent mitotic arrest...
March 9, 2018: Oncogene
Mladen Korbelik
The insult delivered by photodynamic therapy (PDT) in treated cells is oxidative stress. The main burden threatening survival of PDT-treated cells is proteotoxic damage that jeopardizes proteostasis in these cells. For dealing with this type of proteostasis impairment, cells have developed protection mechanisms operating by signaling networks. This review will outline various components of signaling networks that can be engaged in stressed cells with highlighting the emerging aspects relevant to response to PDT...
March 7, 2018: Lasers in Surgery and Medicine
Young Dong Yoo, Su Ran Mun, Chang Hoon Ji, Ki Woon Sung, Keum Young Kang, Ah Jung Heo, Su Hyun Lee, Jee Young An, Joonsung Hwang, Xiang-Qun Xie, Aaron Ciechanover, Bo Yeon Kim, Yong Tae Kwon
The conjugation of amino acids to the protein N termini is universally observed in eukaryotes and prokaryotes, yet its functions remain poorly understood. In eukaryotes, the amino acid l-arginine (l-Arg) is conjugated to N-terminal Asp (Nt-Asp), Glu, Gln, Asn, and Cys, directly or associated with posttranslational modifications. Following Nt-arginylation, the Nt-Arg is recognized by UBR boxes of N-recognins such as UBR1, UBR2, UBR4/p600, and UBR5/EDD, leading to substrate ubiquitination and proteasomal degradation via the N-end rule pathway...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Matthew Dodson, Pengfei Liu, Tao Jiang, Andrew J Ambrose, Gang Luo, Montserrat Rojo de la Vega, Aram B Cholanians, Pak Kin Wong, Eli Chapman, Donna D Zhang
Environmental exposure to arsenic is linked to adverse health effects including cancer and diabetes. Pleiotropic cellular effects are observed with arsenic exposure. Previously, we demonstrated that arsenic dysregulated the autophagy pathway at low, environmentally relevant concentrations. Here, we show that arsenic blocks autophagy by preventing autophagosome-lysosome fusion. Specifically, arsenic disrupts formation of the STX17-SNAP29-VAMP8 SNARE complex, where SNAP29 mediates vesicle fusion through bridging STX17-containing autophagosomes to VAMP8-bearing lysosomes...
March 5, 2018: Molecular and Cellular Biology
Tsukasa Okiyoneda, Guido Veit, Ryohei Sakai, Misaki Aki, Takeshi Fujihara, Momoko Higashi, Seiko Susuki-Miyata, Masanori Miyata, Norihito Fukuda, Akihiko Yoshida, Haijin Xu, Pirjo M Apaja, Gergely L Lukacs
The peripheral protein quality control (QC) system removes non-native membrane proteins, including ΔF508-CFTR, the most common CFTR mutant in cystic fibrosis (CF), from the plasma membrane (PM) for lysosomal degradation by ubiquitination. It remains unclear how unfolded membrane proteins are recognized and targeted for ubiquitination and how they are removed from the apical PM. Using comprehensive siRNA screens, we identified RFFL, an E3 ubiquitin (Ub) ligase that directly and selectively recognizes unfolded ΔF508-CFTR through its disordered regions...
February 22, 2018: Developmental Cell
Nadinath B Nillegoda, Anne S Wentink, Bernd Bukau
Protein aggregates are formed in cells with profoundly perturbed proteostasis, where the generation of misfolded proteins exceeds the cellular refolding and degradative capacity. They are a hallmark of protein conformational disorders and aged and/or environmentally stressed cells. Protein aggregation is a reversible process in vivo, which counteracts proteotoxicities derived from aggregate persistence, but the chaperone machineries involved in protein disaggregation in Metazoa were uncovered only recently...
February 28, 2018: Trends in Biochemical Sciences
Maria J Perez-Alvarez, Mario Villa Gonzalez, Irene Benito-Cuesta, Francisco G Wandosell
Intense efforts are being undertaken to understand the pathophysiological mechanisms triggered after brain ischemia and to develop effective pharmacological treatments. However, the underlying molecular mechanisms are complex and not completely understood. One of the main problems is the fact that the ischemic damage is time-dependent and ranges from negligible to massive, involving different cell types such as neurons, astrocytes, microglia, endothelial cells, and some blood-derived cells (neutrophils, lymphocytes, etc...
2018: Frontiers in Neuroscience
Nur Hidayah Jamar, Paraskevi Kritsiligkou, Chris M Grant
Eukaryotic cells contain translation-associated mRNA surveillance pathways which prevent the production of potentially toxic proteins from aberrant mRNA translation events. We found that loss of mRNA surveillance pathways in mutants deficient in nonsense-mediated decay (NMD), no-go decay (NGD) and nonstop decay (NSD) results in increased protein aggregation. We have isolated and identified the proteins that aggregate and our bioinformatic analyses indicates that increased aggregation of aggregation-prone proteins is a general occurrence in mRNA surveillance mutants, rather than being attributable to specific pathways...
March 1, 2018: Scientific Reports
Colin Adrain, Sivan Henis-Korenblit, Pedro M Domingos
It was a sunny Ericeira, in Portugal, that received the participants of the EMBO Workshop on Proteostasis, from 17 to 21 November 2017. Most participants gave talks or presented posters concerning their most recent research results, and lively scientific discussions occurred against the backdrop of the beautiful Atlantic Ocean.Proteostasis is the portmanteau of the words protein and homeostasis, and it refers to the biological mechanisms controlling the biogenesis, folding, trafficking and degradation of proteins in cells...
March 1, 2018: Journal of Cell Science
Chloé Sauzay, Christophe Louandre, Sandra Bodeau, Frédéric Anglade, Corinne Godin, Zuzana Saidak, Jean-Xavier Fontaine, Cédric Usureau, Nathalie Martin, Roland Molinie, Julie Pascal, François Mesnard, Olivier Pluquet, Antoine Galmiche
Sorafenib is the first line treatment for advanced hepatocellular carcinoma (HCC). We explored its impact on the proteostasis of cancer cells, i.e. the processes that regulate the synthesis, maturation and turn-over of cellular proteins. We observed that sorafenib inhibits the production of the tumour marker alpha-foetoprotein (AFP) in two different HCC cell lines, an effect that correlated with a radical inhibition of protein biosynthesis. This effect was observed at clinically relevant concentrations of sorafenib and was not related to the effect of sorafenib on the transport of amino acids across the plasma membrane or the induction of the unfolded protein response (UPR)...
February 2, 2018: Oncotarget
Ladan Khodaparast, Laleh Khodaparast, Rodrigo Gallardo, Nikolaos N Louros, Emiel Michiels, Reshmi Ramakrishnan, Meine Ramakers, Filip Claes, Lydia Young, Mohammad Shahrooei, Hannah Wilkinson, Matyas Desager, Wubishet Mengistu Tadesse, K Peter R Nilsson, Per Hammarström, Abram Aertsen, Sebastien Carpentier, Johan Van Eldere, Frederic Rousseau, Joost Schymkowitz
Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find that most APRs are unique within a proteome, but that a small minority of APRs occur in many proteins. When aggregation is nucleated in bacteria by such frequently occurring APRs, it leads to massive and lethal inclusion body formation containing a large number of proteins. Buildup of bacterial resistance against these peptides is slow...
February 28, 2018: Nature Communications
Qi Zhang, Cheng Ma, Marla Gearing, Peng George Wang, Lih-Shen Chin, Lian Li
Although the genetic causes for several rare, familial forms of Alzheimer's disease (AD) have been identified, the etiology of the sporadic form of AD remains unclear. Here, we report a systems-level study of disease-associated proteome changes in human frontal cortex of sporadic AD patients using an integrated approach that combines mass spectrometry-based quantitative proteomics, differential expression analysis, and co-expression network analysis. Our analyses of 16 human brain tissues from AD patients and age-matched controls showed organization of the cortical proteome into a network of 24 biologically meaningful modules of co-expressed proteins...
March 1, 2018: Acta Neuropathologica Communications
Elan W Silverblatt-Buser, Melissa A Frick, Christina Rabeler, Nicholas J Kaplinsky
Protein folding and degradation are both required for protein quality control, an essential cellular activity that underlies normal growth and development. We investigated how BOB1 , an Arabidopsis thaliana small heat shock protein, maintains normal plant development. bob1 mutants exhibit organ polarity defects and have expanded domains of KNOX gene expression. Some of these phenotypes are ecotype specific suggesting that other genes function to modify them. Using a reverse genetic approach we identified an interaction between BOB1 and FIL , a gene required for abaxial organ identity...
February 27, 2018: G3: Genes—Genomes—Genetics
Tammy Ryan, Vladimir V Bamm, Morgan G Stykel, Carla L Coackley, Kayla M Humphries, Rhiannon Jamieson-Williams, Rajesh Ambasudhan, Dick D Mosser, Stuart A Lipton, George Harauz, Scott D Ryan
Neuronal loss in Parkinson's disease (PD) is associated with aberrant mitochondrial function and impaired proteostasis. Identifying the mechanisms that link these pathologies is critical to furthering our understanding of PD pathogenesis. Using human pluripotent stem cells (hPSCs) that allow comparison of cells expressing mutant SNCA (encoding α-synuclein (α-syn)) with isogenic controls, or SNCA-transgenic mice, we show that SNCA-mutant neurons display fragmented mitochondria and accumulate α-syn deposits that cluster to mitochondrial membranes in response to exposure of cardiolipin on the mitochondrial surface...
February 26, 2018: Nature Communications
Peter P Rainer, Peihong Dong, Matteo Sorge, Justyna Fert-Bober, Ronald J Holewinski, Yuchuan Wang, Catherine Foss, Steven S An, Alessandra Baracca, Giancarlo Solaini, Charles Glabe, Martin G Pomper, Jennifer E Van Eyk, Gordon F Tomaselli, Nazareno Paolocci, Giulio Agnetti
<u>Rationale:</u> Disrupted proteostasis is one major pathological trait that heart failure (HF) shares with other organ proteinopathies, such as Alzheimer's and Parkinson's diseases. Yet, differently from the latter, whether and how cardiac preamyloid oligomers (PAOs) develop in acquired forms of HF is unclear. <u>Objective:</u> We previously reported a rise in mono-phosphorylated, aggregate-prone desmin in canine and human HF. We now tested if mono-phosphorylated desmin acts as the seed nucleating PAOs formation and determined if positron emission tomography (PET) is able to detect myocardial PAOs in non-genetic HF...
February 26, 2018: Circulation Research
Daniel Hughes, Giovanna R Mallucci
The unfolded protein response (UPR) is a highly conserved protein quality control mechanism, activated in response to Endoplasmic Reticulum (ER) stress. Signaling is mediated through three branches, PERK, IRE1 and ATF6, respectively, that together provide a coordinated response that contributes to overcoming disrupted proteostasis. PERK branch activation predominantly causes a rapid reduction in global rates of translation, whilst the IRE1 and ATF6 branch signaling induce a transcriptional response resulting in expression of chaperones and components of the protein degradation machinery...
February 24, 2018: FEBS Journal
Yu Liu, Kun Miao, Yinghao Li, Matthew Fares, Shuyuan Chen, Xin Zhang
Protein homeostasis, or proteostasis, is essential for cellular fitness and viability. Many environmental factors compromise proteostasis, induce global proteome stress, and cause diseases. Proteome stress sensor is a powerful tool to dissect the mechanism of cellular stress and find therapeutics that ameliorate these diseases. In this work, we present a multi-color HaloTag-based sensor (named AgHalo) to visualize and quantify proteome stresses in live cells. The current AgHalo sensor is equipped with three fluorogenic probes that turn on fluorescence when the sensor forms either soluble oligomers or insoluble aggregates upon exposure to stress conditions, both in vitro and in cellulo...
February 23, 2018: Biochemistry
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