Could Small Heat Shock Protein HSP27 Be a First-Line Target for Preventing Protein Aggregation in Parkinson’S Disease?
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The HECT Domain Ubiquitin Ligase HUWE1 Targets Unassembled Soluble Proteins for Degradation
OPEN Citation: Cell Discovery (2016) 2, 16040; doi:10.1038/celldisc.2016.40 ARTICLE www.nature.com/celldisc The HECT domain ubiquitin ligase HUWE1 targets unassembled soluble proteins for degradation Yue Xu1, D Eric Anderson2, Yihong Ye1 1Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; 2Advanced Mass Spectrometry Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA In eukaryotes, many proteins function in multi-subunit complexes that require proper assembly. To maintain complex stoichiometry, cells use the endoplasmic reticulum-associated degradation system to degrade unassembled membrane subunits, but how unassembled soluble proteins are eliminated is undefined. Here we show that degradation of unassembled soluble proteins (referred to as unassembled soluble protein degradation, USPD) requires the ubiquitin selective chaperone p97, its co-factor nuclear protein localization protein 4 (Npl4), and the proteasome. At the ubiquitin ligase level, the previously identified protein quality control ligase UBR1 (ubiquitin protein ligase E3 component n-recognin 1) and the related enzymes only process a subset of unassembled soluble proteins. We identify the homologous to the E6-AP carboxyl terminus (homologous to the E6-AP carboxyl terminus) domain-containing protein HUWE1 as a ubiquitin ligase for substrates bearing unshielded, hydrophobic segments. We used a stable isotope labeling with amino acids-based proteomic approach to identify endogenous HUWE1 substrates. Interestingly, many HUWE1 substrates form multi-protein com- plexes that function in the nucleus although HUWE1 itself is cytoplasmically localized. Inhibition of nuclear entry enhances HUWE1-mediated ubiquitination and degradation, suggesting that USPD occurs primarily in the cytoplasm. -
Identification of the Binding Partners for Hspb2 and Cryab Reveals
Brigham Young University BYU ScholarsArchive Theses and Dissertations 2013-12-12 Identification of the Binding arP tners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactions and Non- Redundant Roles for Small Heat Shock Proteins Kelsey Murphey Langston Brigham Young University - Provo Follow this and additional works at: https://scholarsarchive.byu.edu/etd Part of the Microbiology Commons BYU ScholarsArchive Citation Langston, Kelsey Murphey, "Identification of the Binding Partners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactions and Non-Redundant Roles for Small Heat Shock Proteins" (2013). Theses and Dissertations. 3822. https://scholarsarchive.byu.edu/etd/3822 This Thesis is brought to you for free and open access by BYU ScholarsArchive. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of BYU ScholarsArchive. For more information, please contact [email protected], [email protected]. Identification of the Binding Partners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactions and Non-Redundant Roles for Small Heat Shock Proteins Kelsey Langston A thesis submitted to the faculty of Brigham Young University in partial fulfillment of the requirements for the degree of Master of Science Julianne H. Grose, Chair William R. McCleary Brian Poole Department of Microbiology and Molecular Biology Brigham Young University December 2013 Copyright © 2013 Kelsey Langston All Rights Reserved ABSTRACT Identification of the Binding Partners for HspB2 and CryAB Reveals Myofibril and Mitochondrial Protein Interactors and Non-Redundant Roles for Small Heat Shock Proteins Kelsey Langston Department of Microbiology and Molecular Biology, BYU Master of Science Small Heat Shock Proteins (sHSP) are molecular chaperones that play protective roles in cell survival and have been shown to possess chaperone activity. -
45–54 Physical Location of Genes
Rocz. Nauk. Zoot., T. 44, z. 1 (2017) 45–54 PHYSICAL LOCATION OF GENES ENCODING SMALL HEAT SHOCK PROTEINS IN THE SUIDAE GENOMES* * Barbara Danielak-Czech1 , Anna Kozubska-Sobocińska1 , Marek Babicz2 1National Research Institute of Animal Production, Department of Animal Genomics and Molecular Biology, 32-083 Balice n. Kraków, Poland 2University of Life Sciences in Lublin, Faculty of Biology, Animal Sciences and Bioeconomy, Akademicka 13, 20-950 Lublin, Poland The subject of the studies carried out was physical mapping of the HSPB1, HSPB2, CRY- AB (alternative name HSPB5), HSPB6 and HSPB8 genes from the family of small heat shock protein genes (HSPB) on chromosomes of the domestic pig (Sus scrofa domestica) and European wild pig (Sus scrofa scrofa). The application of FISH technique with pro- bes derived from porcine BAC clones: CH242-237N5, CH242-333E2, CH242-173G9 and CH242-102C8 made it possible to determine the location of the studied genes, respectively, in 3p15, 9p21, 6q12 and 14q21 genome regions of domestic and wild pigs. The physical localization of HSPB genes allowed assigning these loci to the linkage and syntenic groups of genes in Suidae. Precise, molecular and cytogenetic identification of genes responsible for resistance to stress and disease, and determining meat production is essential for the genetic selection effects, aimed to reduce mortality causing significant economic loss in animal production. The studies performed may help to elucidate the role of the HSPB genes in protection against pathogenic or environmental stress, affecting pigs’ survivability and meat quality. Key words: Suidae, FISH, HSPB genes, muscle development, meat quality Small heat shock proteins (HSPB) are the smallest, most variable in size, class of the multigene heat shock protein (HSP) family, having molecular masses ranging approximately from 15 to 30 kDa and the α-crystallin domains (~85 amino acids residues) in the highly conserved C-terminal protein regions. -
Heat Shock Protein 27 Inhibits HMGB1 Translocation by Regulating CBP
Molecular Immunology 108 (2019) 45–55 Contents lists available at ScienceDirect Molecular Immunology journal homepage: www.elsevier.com/locate/molimm Heat shock protein 27 inhibits HMGB1 translocation by regulating CBP acetyltransferase activity and ubiquitination T ⁎⁎ Xiaowen Bia, Miao Xua, Jinfei Lia, Ting Huanga, Baolin Jianga, Lei Shena, Lan Luob, , ⁎⁎⁎ ⁎ Shixiang Liuc, , Zhimin Yina, a Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, PR China b State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, PR China c Jurong People’s Hospital, Zhenjiang, Jiangsu, PR China ARTICLE INFO ABSTRACT Keywords: Heat-shock protein 27 (Hsp27) is a member of the small heat shock protein family that has been reported to Hsp27 protect cells against pro-inflammatory stresses. High mobility group box 1 (HMGB1) is a proinflammatory cy- CBP tokine associated with death from sepsis and other inflammatory diseases. After being acetylated by CREB- HMGB1 binding protein (CBP), the transcriptional adaptor and acetyltransferase, HMGB1 translocates from the nucleus Phosphorylation to the cytoplasm. In the present study, we investigated the effects of Hsp27 on HMGB1 translocation from the Acetylation nucleus to the cytoplasm in THP-1 cells. We found that Hsp27 phosphorylation decreased LPS-induced HMGB1 acetylation and translocation from the nucleus to the cytoplasm, as well as its release from THP-1 cells. The study further showed that cytosolic non-phosphorylated Hsp27 enhanced CBP ubiquitination and degradation in LPS-unstimulated cells, which suggested that Hsp27 maintained suitable CBP levels under normal physiological conditions. After LPS stimulation, Hsp27 was phosphorylated at serine residues 15/78 and translocated from the cytoplasm into the nucleus. -
Decreased Expression of Heat Shock Protein 70 Mrna and Protein After Heat Treatment in Cells of Aged Rats
Proc. Nati. Acad. Sci. USA Vol. 87, pp. 846-850, January 1990 Cell Biology Decreased expression of heat shock protein 70 mRNA and protein after heat treatment in cells of aged rats (stress/aging) JOSEPH FARGNOLI*, TAKAHIRO KUNISADA*, ALBERT J. FORNACE, JR.t, EDWARD L. SCHNEIDER*, AND NIKKI J. HOLBROOK*f *Laboratory of Molecular Genetics, National Institute on Aging, 4940 Eastern Avenue, Baltimore, MD 21224; and tRadiation Oncology Branch, National Cancer Institute, Bethesda, MD 20892 Communicated by David M. Prescott, November 2, 1989 ABSTRACT The effect of aging on the induction of heat primary fibroblasts with aging. Furthermore, in additional shock protein 70 (HSP70)-encoding gene expression by elevated experiments with fresh lung tissue from old and young rats, temperatures was studied in cultures of lung- or skin-derived we found a similar age-related decline in HSP70 expression fibroblasts from young (5 mo) and old (24 mo) male Wistar in response to heat stress. rats. Although the kinetics of the heat shock response were found to be similar in the two age groups, we observed lower levels of induction of HSP70 mRNA and HSP70 protein in MATERIALS AND METHODS confluent primary lung and skin fibroblast cultures derived Isolation and Culture ofPrimary Rat Fibroblasts. Fibroblast from aged animals. Additional experiments with freshly ex- cultures were derived from male Wistar rats obtained from cised lung tissue showed a similar age-related decline in the the Gerontology Research Center animal colony at the Na- heat-induced expression of HSP70. tional Institute on Aging. The lifespan of these animals is 27-28 mo, and the average life expectancy is 24 mo. -
The Growing World of Small Heat Shock Proteins: from Structure to Functions
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Research Online University of Wollongong Research Online Illawarra Health and Medical Research Institute Faculty of Science, Medicine and Health 2017 The growing world of small heat shock proteins: from structure to functions Serena Carra University of Modena and Reggio Emilia Simon Alberti Max Planck Institute Patrick Arrigo Universite de Lyon Justin Benesch Oxford University Ivor Benjamin University of Utah See next page for additional authors Follow this and additional works at: https://ro.uow.edu.au/ihmri Part of the Medicine and Health Sciences Commons Recommended Citation Carra, Serena; Alberti, Simon; Arrigo, Patrick; Benesch, Justin; Benjamin, Ivor; Boelens, Wilbert C.; Bartelt- Kirbach, Britta; Brundel, Bianca; Buchner, Johannes; Bukau, Bernd; Carver, John A.; Ecroyd, Heath; Emanuelsson, Cecilia; Finet, Stephanie; Golenhofen, Nikola; Goloubinoff, Pierre; Gusev, Nikolai; Haslbeck, Martin; Hightower, Lawrence; Kampinga, Harm; Klevit, Rachel; Liberek, Krzysztof; Mchaourab, Hassane; McMenimen, Kathryn; Poletti, Angelo; Quinlan, Roy; Strelkov, Sergei; Toth, Melinda; Vierling, Elizabeth; and Tanguay, Robert, "The growing world of small heat shock proteins: from structure to functions" (2017). Illawarra Health and Medical Research Institute. 1251. https://ro.uow.edu.au/ihmri/1251 Research Online is the open access institutional repository for the University of Wollongong. For further information contact the UOW Library: [email protected] The growing world of small heat shock proteins: from structure to functions Abstract Small heat shock proteins (sHSPs) are present in all kingdoms of life and play fundamental roles in cell biology. sHSPs are key components of the cellular protein quality control system, acting as the first line of defense against conditions that affect protein homeostasis and proteome stability, from bacteria to plants to humans. -
Genome-Wide Sirna Screen for Mediators of NF-Κb Activation
Genome-wide siRNA screen for mediators SEE COMMENTARY of NF-κB activation Benjamin E. Gewurza, Fadi Towficb,c,1, Jessica C. Marb,d,1, Nicholas P. Shinnersa,1, Kaoru Takasakia, Bo Zhaoa, Ellen D. Cahir-McFarlanda, John Quackenbushe, Ramnik J. Xavierb,c, and Elliott Kieffa,2 aDepartment of Medicine and Microbiology and Molecular Genetics, Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; bCenter for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; cProgram in Medical and Population Genetics, The Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142; dDepartment of Biostatistics, Harvard School of Public Health, Boston, MA 02115; and eDepartment of Biostatistics and Computational Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115 Contributed by Elliott Kieff, December 16, 2011 (sent for review October 2, 2011) Although canonical NFκB is frequently critical for cell proliferation, (RIPK1). TRADD engages TNFR-associated factor 2 (TRAF2), survival, or differentiation, NFκB hyperactivation can cause malig- which recruits the ubiquitin (Ub) E2 ligase UBC5 and the E3 nant, inflammatory, or autoimmune disorders. Despite intensive ligases cIAP1 and cIAP2. CIAP1/2 polyubiquitinate RIPK1 and study, mammalian NFκB pathway loss-of-function RNAi analyses TRAF2, which recruit and activate the K63-Ub binding proteins have been limited to specific protein classes. We therefore under- TAB1, TAB2, and TAB3, as well as their associated kinase took a human genome-wide siRNA screen for novel NFκB activa- MAP3K7 (TAK1). TAK1 in turn phosphorylates IKKβ activa- tion pathway components. Using an Epstein Barr virus latent tion loop serines to promote IKK activity (4). -
The Evolutionary and Ecological Role of Heat Shock Proteins
Ecology Letters, (2003) 6: 1025–1037 doi: 10.1046/j.1461-0248.2003.00528.x REVIEW The evolutionary and ecological role of heat shock proteins Abstract Jesper Givskov Sørensen1*, Most heat shock proteins (Hsp) function as molecular chaperones that help organisms to Torsten Nygaard Kristensen1,2 cope with stress of both an internal and external nature. Here, we review the recent and Volker Loeschcke1 evidence of the relationship between stress resistance and inducible Hsp expression, 1 Department of Ecology and including a characterization of factors that induce the heat shock response and a Genetics, Aarhus Centre for discussion of the associated costs. We report on studies of stress resistance including Environmental Stress Research mild stress, effects of high larval densities, inbreeding and age on Hsp expression, as well (ACES), University of Aarhus, Ny as on natural variation in the expression of Hsps. The relationship between Hsps and life Munkegade, Aarhus C, Denmark 2 history traits is discussed with special emphasis on the ecological and evolutionary Department of Animal Breeding and Genetics, Danish relevance of Hsps. It is known that up-regulation of the Hsps is a common cellular Institute of Agricultural response to increased levels of non-native proteins that facilitates correct protein Sciences, Tjele, Denmark folding/refolding or degradation of non-functional proteins. However, we also suggest *Correspondence: E-mail: that the expression level of Hsp in each species and population is a balance between [email protected] benefits and costs, i.e. a negative impact on growth, development rate and fertility as a result of overexpression of Hsps. -
Deletion Variant Against Age-Related Macular Degeneration In
Laboratory Investigation (2017) 97, 43–52 © 2017 USCAP, Inc All rights reserved 0023-6837/17 Protective effects of an HTRA1 insertion–deletion variant against age-related macular degeneration in the Chinese populations Tsz Kin Ng1, Xiao Ying Liang1, Fang Lu2,3, David TL Liu1, Gary HF Yam1,LiMa1, Pancy OS Tam1, Haoyu Chen4, Ling Ping Cen4, Li Jia Chen1, Zhenglin Yang2,3 and Chi Pui Pang1 Age-related macular degeneration (AMD) is a leading cause of visual impairment and irreversible blindness in most developed countries, affecting about 50 million elderly people worldwide. Retinal pigment epithelial (RPE) cell degeneration is the pathophysiological cause of AMD, leading to geographic atrophy and choroidal neovascularization. We and others have previously identified several polymorphisms on chromosome 10q26 (HTRA1 rs11200638 as well as LOC387715 rs10490924 and c.372_815del443ins54) associated with AMD. In this study, we confirmed the association of our previously identified HTRA1 insertion–deletion (indel) variant (c.34delCinsTCCT) in 195 exudative AMD patients and 390 controls from the Hong Kong Chinese cohort with additional 168 patients and 210 controls from the Chengdu Chinese cohort and followed by studying its biological functions in RPE cells. Genetic analysis verified the higher prevalence of c.34delCinsTCCT allele in control subjects (8.0%) than in AMD patients (1.9%; P = 7.87 × 10 − 5, odds ratio = 0.229). This protective effect was validated as the haplotype of the c.34delCinsTCCT allele existed independent of the risk haplotype (P = 1.17 × 10 − 5). In vitro studies showed that recombinant HTRA1 c.34delCinsTCCT variant protein was more localized in the endoplasmic reticulum of RPE cells compared with the wild-type protein, and its secretion was delayed. -
At Elevated Temperatures, Heat Shock Protein Genes Show Altered Ratios Of
EXPERIMENTAL AND THERAPEUTIC MEDICINE 22: 900, 2021 At elevated temperatures, heat shock protein genes show altered ratios of different RNAs and expression of new RNAs, including several novel HSPB1 mRNAs encoding HSP27 protein isoforms XIA GAO1,2, KEYIN ZHANG1,2, HAIYAN ZHOU3, LUCAS ZELLMER4, CHENGFU YUAN5, HAI HUANG6 and DEZHONG JOSHUA LIAO2,6 1Department of Pathology, Guizhou Medical University Hospital; 2Key Lab of Endemic and Ethnic Diseases of The Ministry of Education of China in Guizhou Medical University; 3Clinical Research Center, Guizhou Medical University Hospital, Guiyang, Guizhou 550004, P.R. China; 4Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA; 5Department of Biochemistry, China Three Gorges University, Yichang, Hubei 443002; 6Center for Clinical Laboratories, Guizhou Medical University Hospital, Guiyang, Guizhou 550004, P.R. China Received December 16, 2020; Accepted May 10, 2021 DOI: 10.3892/etm.2021.10332 Abstract. Heat shock proteins (HSP) serve as chaperones genes may engender multiple protein isoforms. These results to maintain the physiological conformation and function of collectively suggested that, besides increasing their expres‑ numerous cellular proteins when the ambient temperature is sion, certain HSP and associated genes also use alternative increased. To determine how accurate the general assumption transcription start sites to produce multiple RNA transcripts that HSP gene expression is increased in febrile situations is, and use alternative splicing of a transcript to produce multiple the RNA levels of the HSF1 (heat shock transcription factor 1) mature RNAs, as important mechanisms for responding to an gene and certain HSP genes were determined in three cell increased ambient temperature in vitro. lines cultured at 37˚C or 39˚C for three days. -
Genome-Wide DNA Methylation Map of Human Neutrophils Reveals Widespread Inter-Individual Epigenetic Variation
www.nature.com/scientificreports OPEN Genome-wide DNA methylation map of human neutrophils reveals widespread inter-individual Received: 15 June 2015 Accepted: 29 October 2015 epigenetic variation Published: 27 November 2015 Aniruddha Chatterjee1,2, Peter A. Stockwell3, Euan J. Rodger1, Elizabeth J. Duncan2,4, Matthew F. Parry5, Robert J. Weeks1 & Ian M. Morison1,2 The extent of variation in DNA methylation patterns in healthy individuals is not yet well documented. Identification of inter-individual epigenetic variation is important for understanding phenotypic variation and disease susceptibility. Using neutrophils from a cohort of healthy individuals, we generated base-resolution DNA methylation maps to document inter-individual epigenetic variation. We identified 12851 autosomal inter-individual variably methylated fragments (iVMFs). Gene promoters were the least variable, whereas gene body and upstream regions showed higher variation in DNA methylation. The iVMFs were relatively enriched in repetitive elements compared to non-iVMFs, and were associated with genome regulation and chromatin function elements. Further, variably methylated genes were disproportionately associated with regulation of transcription, responsive function and signal transduction pathways. Transcriptome analysis indicates that iVMF methylation at differentially expressed exons has a positive correlation and local effect on the inclusion of that exon in the mRNA transcript. Methylation of DNA is a mechanism for regulating gene function in all vertebrates. It has a role in gene silencing, tissue differentiation, genomic imprinting, chromosome X inactivation, phenotypic plasticity, and disease susceptibility1,2. Aberrant DNA methylation has been implicated in the pathogenesis of sev- eral human diseases, especially cancer3–5. Variation in DNA methylation patterns in healthy individuals has been hypothesised to alter human phenotypes including susceptibility to common diseases6 and response to drug treatments7. -
Supplementary Materials
Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine