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1.
Nat Commun ; 14(1): 8427, 2023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38114459

RESUMO

Phenology, the seasonal timing of life events, is an essential component of diversity patterns. However, the mechanisms involved are complex and understudied. Body colour may be an important factor, because dark-bodied species absorb more solar radiation, which is predicted by the Thermal Melanism Hypothesis to enable them to thermoregulate successfully in cooler temperatures. Here we show that colour lightness of dragonfly assemblages varies in response to seasonal changes in solar radiation, with darker early- and late-season assemblages and lighter mid-season assemblages. This finding suggests a link between colour-based thermoregulation and insect phenology. We also show that the phenological pattern of dragonfly colour lightness advanced over the last decades. We suggest that changing seasonal temperature patterns due to global warming together with the static nature of solar radiation may drive dragonfly flight periods to suboptimal seasonal conditions. Our findings open a research avenue for a more mechanistic understanding of phenology and spatio-phenological impacts of climate warming on insects.


Assuntos
Odonatos , Animais , Estações do Ano , Clima , Temperatura , Insetos , Mudança Climática
2.
Nat Commun ; 14(1): 8117, 2023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38114472

RESUMO

Small-scale studies have shown that colour lightness variation can have important physiological implications in ectotherms, with darker species having greater heating rates, as well as protection against pathogens and photooxidative damage. Using data for 41% (3059) of all known frog and toad species (Anura) from across the world, we reveal ubiquitous and strong clines of decreasing colour lightness towards colder regions and regions with higher pathogen pressure and UVB radiation. The relative importance of pathogen resistance is higher in the tropics and that of thermoregulation is higher in temperate regions. The results suggest that these functions influence colour lightness evolution in anurans and filtered for more similarly coloured species under climatic extremes, while their concurrent importance resulted in high within-assemblage variation in productive regions. Our findings indicate three important functions of colour lightness in anurans - thermoregulation, pathogen and UVB protection - and broaden support for colour lightness-environment relationships in ectotherms.


Assuntos
Anuros , Regulação da Temperatura Corporal , Animais , Cor , Anuros/fisiologia
3.
Trends Ecol Evol ; 38(12): 1143-1153, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37684131

RESUMO

All aspects of biodiversity research, from taxonomy to conservation, rely on data associated with species names. Effective integration of names across multiple fields is paramount and depends on the coordination and organization of taxonomic data. We assess current efforts and find that even key applications for well-studied taxa still lack commonality in taxonomic information required for integration. We identify essential taxonomic elements from our interoperability assessment to support improved access and integration of taxonomic data. A stronger focus on these elements has the potential to involve taxonomic communities in biodiversity science and overcome broken linkages currently limiting research capacity. We encourage a community effort to democratize taxonomic expertise and language in order to facilitate maximum interoperability and integration.


Assuntos
Biodiversidade , Classificação , Conservação dos Recursos Naturais
4.
Ecol Evol ; 12(11): e9465, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36381396

RESUMO

Insect populations have become increasingly threatened during the last decades due to climate change and landuse intensification. Species characteristics driving these threats remain poorly understood. Trait-based analyses provide a straight-forward approach to gain a mechanistic understanding of species' extinction risk, guiding the development of conservation strategies. We combined morphological traits and phylogenetic relationship for 332 European species of butterflies and 115 species of odonates (dragon and damselflies) to model their red list status via phylogenetically controlled ordered logistic regression. We hypothesized that extinction risk increases with increasing body volume and wing area, decreasing range size, and is larger for brighter species. All investigated traits exhibited a strong phylogenetic signal. When controlling for phylogenetic relationship, we found that extinction risk of butterflies increased with decreasing range size. The extinction risk of odonates showed no relationship with the selected traits. Our results show that there is no universal trait defining the extinction risk of our investigated insect taxa. Furthermore, evolutionary history, measured as the phylogenetically predicted part of our analyzed traits, poorly predicted extinction risk. Our study confirms the focus of conservation measures on European butterfly species with small range sizes.

5.
Glob Chang Biol ; 28(13): 3998-4012, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35535680

RESUMO

Recent climate and land-use changes are having substantial impacts on biodiversity, including population declines, range shifts, and changes in community composition. However, few studies have compared these impacts among multiple taxa, particularly because of a lack of standardized time series data over long periods. Existing data sets are typically of low resolution or poor coverage, both spatially and temporally, thereby limiting the inferences that can be drawn from such studies. Here, we compare climate and land-use driven occupancy changes in butterflies, grasshoppers, and dragonflies using an extensive data set of highly heterogeneous observation data collected in the central European region of Bavaria (Germany) over a 40-year period. Using occupancy models, we find occupancies (the proportion of sites occupied by a species in each year) of 37% of species have decreased, 30% have increased and 33% showed no significant trend. Butterflies and grasshoppers show strongest declines with 41% of species each. By contrast, 52% of dragonfly species increased. Temperature preference and habitat specificity appear as significant drivers of species trends. We show that cold-adapted species across all taxa have declined, whereas warm-adapted species have increased. In butterflies, habitat specialists have decreased, while generalists increased or remained stable. The trends of habitat generalists and specialists both in grasshoppers and semi-aquatic dragonflies, however did not differ. Our findings indicate strong and consistent effects of climate warming across insect taxa. The decrease of butterfly specialists could hint towards a threat from land-use change, as especially butterfly specialists' occurrence depends mostly on habitat quality and area. Our study not only illustrates how these taxa showed differing trends in the past but also provides hints on how we might mitigate the detrimental effects of human development on their diversity in the future.


Assuntos
Borboletas , Odonatos , Animais , Biodiversidade , Clima , Mudança Climática , Ecossistema , Europa (Continente)
6.
Ecol Evol ; 10(16): 8936-8948, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32884669

RESUMO

Previous macrophysiological studies suggested that temperature-driven color lightness and body size variations strongly influence biogeographical patterns in ectotherms. However, these trait-environment relationships scale to local assemblages and the extent to which they can be modified by dispersal remains largely unexplored. We test whether the predictions of the thermal melanism hypothesis and the Bergmann's rule hold for local assemblages. We also assess whether these trait-environment relationships are more important for species adapted to less stable (lentic) habitats, due to their greater dispersal propensity compared to those adapted to stable (lotic) habitats.We quantified the color lightness and body volume of 99 European dragon- and damselflies (Odonata) and combined these trait information with survey data for 518 local assemblages across Europe. Based on this continent-wide yet spatially explicit dataset, we tested for effects temperature and precipitation on the color lightness and body volume of local assemblages and assessed differences in their relative importance and strength between lentic and lotic assemblages, while accounting for spatial and phylogenetic autocorrelation.The color lightness of assemblages of odonates increased, and body size decreased with increasing temperature. Trait-environment relationships in the average and phylogenetic predicted component were equally important for assemblages of both habitat types but were stronger in lentic assemblages when accounting for phylogenetic autocorrelation.Our results show that the mechanism underlying color lightness and body size variations scale to local assemblages, indicating their general importance. These mechanisms were of equal evolutionary significance for lentic and lotic species, but higher dispersal ability seems to enable lentic species to cope better with historical climatic changes. The documented differences between lentic and lotic assemblages also highlight the importance of integrating interactions of thermal adaptations with proxies of the dispersal ability of species into trait-based models, for improving our understanding of climate-driven biological responses.

7.
Ecology ; 101(10): e03121, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33460060

RESUMO

Individuals of large or dark-colored ectothermic species often have a higher reproduction and activity than small or light-colored ones. However, investments into body size or darker colors should negatively affect the fitness of individuals as they increase their growth and maintenance costs. Thus, it is unlikely that morphological traits directly affect species' distribution and abundance. Yet, this simplification is frequently made in trait-based ecological analyses. Here, we integrated the energy allocation strategies of species into an ecophysiological framework to explore the mechanisms that link species' morphological traits and population dynamics. We hypothesized that the effects of morphological traits on species' distribution and abundance are not direct but mediated by components of the energy budget and that species can allocate more energy towards dispersal and reproduction if they compensate their energetic costs by reducing mobility costs or increasing energy uptake. To classify species' energy allocation strategies, we used easily measured proxies for the mobility costs and energy uptake of butterflies that can be also applied to other taxa. We demonstrated that contrasting effects of morphological traits on distribution and abundance of butterfly species offset each other when species' energy allocation strategies are not taken into account. Larger and darker butterfly species had wider distributions and were more abundant if they compensated the investment into body size and color darkness (i.e., melanin) by reducing their mobility costs or increasing energy uptake. Adults of darker species were more mobile and foraged less compared to lighter colored ones, if an investment into melanin was indirectly compensated via a size-dependent reduction of mobility costs or increase of energy uptake. Our results indicate that differences in the energy allocations strategies of species account for a considerable part of the variation in species' distribution and abundance that is left unexplained by morphological traits alone and ignoring these differences can lead to false mechanistic conclusions. Therefore, our findings highlight the potential of integrating proxies for species' energy allocation strategies into trait-based models not only for understanding the physiological mechanisms underlying variation in species' distribution and abundance, but also for improving predictions of the population dynamics of species.


Assuntos
Borboletas , Metabolismo Energético , Animais , Evolução Biológica , Tamanho Corporal , Dinâmica Populacional
8.
Sci Rep ; 9(1): 1760, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30741964

RESUMO

Melanin-based dark colouration is beneficial for insects as it increases the absorption of solar energy and protects against pathogens. Thus, it is expected that insect colouration is darker in colder regions and in regions with high humidity, where it is assumed that pathogen pressure is highest. These relationships between colour lightness, insect distribution, and climate between taxa and subtaxa across continents have never been tested and compared. Here we analysed the colour lightness of nearly all butterfly species of North America and Europe using the average colour lightness of species occurring within 50 km × 50 km grid cells across both continents as the dependent variable and average insolation, temperature and humidity within grid cells as explanatory variables. We compared the direction, strength and shape of these relationships between butterfly families and continents. On both continents, butterfly assemblages in colder and more humid regions were generally darker coloured than assemblages in warmer and less humid regions. Although these relationships differed in detail between families, overall trends within families on both continents were similar. Our results add further support for the importance of insect colour lightness as a mechanistic adaptation to climate that influences biogeographical patterns of species distributions.


Assuntos
Borboletas , Cor , Pigmentação , Animais , Meio Ambiente , Europa (Continente) , Geografia , Insetos , América do Norte , Característica Quantitativa Herdável
9.
Curr Biol ; 28(16): R887-R889, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-30130512

RESUMO

Recent results on the thermal biology of unicellular fungi provide evidence that pigmentation is an ancient adaptation for harvesting solar radiation. A new model system promises novel opportunities for quantifying radiative heat transfer and improving biophysical models.


Assuntos
Temperatura Alta , Melaninas , Modelos Biológicos , Pigmentação , Saccharomyces cerevisiae
10.
Oncotarget ; 8(44): 75797-75807, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-29100269

RESUMO

Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation and class switch recombination in mature B-cells, while AID was also shown to play a role in developing pre-BCR/BCR-positive B-cells of the bone marrow. To further elucidate a potential function of Aid in the bone marrow prior to V(D)J-recombination, we utilized an in vivo model which exerts a B-cell developmental arrest at the pro-B cell stage with low frequencies of pro-B cell acute lymphoblastic leukemia (pro-B ALL) development. Therefore, p19Arf-/-Rag1-/- (AR) mice were crossed with Aid-deficient mice (ARA). Surprisingly, loss of Aid expression in pro-B cells accelerated pro-B ALL incidence from 30% (AR) to 98% (ARA). This effect was Aid dose dependent, since Aid+/- animals of the same background displayed a significantly lower incidence (83%). Furthermore, B-cell-specific Aid up-regulation was observed in Aid-competent pro-B ALLs. Additional whole exome/sanger sequencing of murine pro-B ALLs revealed an accumulation of recurrent somatic Jak3 (p.R653H, p.V670A) and Dnm2 (p.G397R) mutations, which highlights the importance of active IL7R signaling in the pro-B ALL blast cells. These findings were further supported by an enhanced proliferative potential of ARA pro-B cells compared to Aid-competent cells from the same genetic background. In summary, we show that both Aid and Rag1 act as a negative regulators in pro-B cells, preventing pro-B ALL.

11.
Zootaxa ; 4272(2): 263-275, 2017 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-28610295

RESUMO

Based on three specimens, the first record of hawker dragonflies from Baltic amber is described in a new genus with two new species: Elektrogomphaeschna peterthieli gen. et sp. nov. and E. annekeae sp. nov.. They belong to the family Gomphaeschnidae and are tentatively attributed to the extinct subfamily Gomphaeschnaoidinae. The latter was previously only known from Cretaceous fossils and is here shown to have survived the K-Pg mass extinction event. This discovery also confirms the still higher diversity of Gomphaeschnidae during the Paleogene compared to the Neogene that was dominated by the more derived Aeshnidae sensu stricto.


Assuntos
Odonatos , Âmbar , Animais , Países Bálticos , Dipterocarpaceae , Fósseis
13.
Neurol Neuroimmunol Neuroinflamm ; 3(4): e241, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27231714

RESUMO

OBJECTIVE: To identify target antigens presented by human leukocyte antigen (HLA)-A*02:01 to the myelin-reactive human T-cell receptor (TCR) 2D1, which was originally isolated from a CD8+ T-cell clone recognizing proteolipid protein (PLP) in the context of HLA-A*03:01, we employed a new antigen search technology. METHODS: We used our recently developed antigen search technology that employs plasmid-encoded combinatorial peptide libraries and a highly sensitive single cell detection system to identify endogenous candidate peptides of mice and human origin. We validated candidate antigens by independent T-cell assays using synthetic peptides and refolded HLA:peptide complexes. A molecular model of HLA-A*02:01:peptide complexes was obtained by molecular dynamics simulations. RESULTS: We identified one peptide from glycerolphosphatidylcholine phosphodiesterase 1, which is identical in mice and humans and originates from a protein that is expressed in many cell types. When bound to HLA-A*02:01, this peptide cross-stimulates the PLP-reactive HLA-A3-restricted TCR 2D1. Investigation of molecular details revealed that the peptide length plays a crucial role in its capacity to bind HLA-A*02:01 and to activate TCR 2D1. Molecular modeling illustrated the 3D structures of activating HLA:peptide complexes. CONCLUSIONS: Our results show that our antigen search technology allows us to identify new candidate antigens of a presumably pathogenic, autoreactive, human CD8+ T-cell-derived TCR. They further illustrate how this TCR, which recognizes a myelin peptide bound to HLA-A*03:01, may cross-react with an unrelated peptide presented by the protective HLA class I allele HLA-A*02:01.

14.
Am J Med Genet A ; 170(6): 1502-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27016154

RESUMO

Intellectual disability (ID) with cerebellar ataxia comprises a genetically heterogeneous group of neurodevelopmental disorders. We identified a homozygous frameshift mutation in CWF19L1 (c.467delC; p.(P156Hfs*33)) by a combination of linkage analysis and Whole Exome Sequencing in a consanguineous Turkish family with a 9-year-old boy affected by early onset cerebellar ataxia and mild ID. Serial MRI showed mildly progressive cerebellar atrophy. Absent C19L1 protein expression in lymphoblastoid cell lines strongly suggested that c.467delC is a disease-causing alteration. One further pregnancy of the mother had been terminated at 22 weeks of gestation because of a small cerebellum and agenesis of corpus callosum. The homozygous CWF19L1 variant was also present in the fetus. Postmortem examination of the fetus in addition showed unilateral hexadactyly and vertebral malformations. These features have not been reported and may represent an expansion of the CWF19L1-related phenotypic spectrum, but could also be due to another, possibly autosomal recessive disorder. The exact function of the evolutionarily highly conserved C19L1 protein is unknown. So far, homozygous or compound heterozygous mutations in CWF19L1 have been identified in two Turkish siblings and a Dutch girl, respectively, affected by cerebellar ataxia and ID. A zebrafish model showed that CWF19L1 loss-of-function mutations result in abnormal cerebellar morphology and movement disorders. Our report corroborates that loss-of-function mutations in CWF19Ll lead to early onset cerebellar ataxia and (progressive) cerebellar atrophy. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Exoma , Sequenciamento de Nucleotídeos em Larga Escala , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Mutação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Encéfalo/anormalidades , Criança , Hibridização Genômica Comparativa , Consanguinidade , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Estudos de Associação Genética , Ligação Genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Radiografia
15.
J Exp Med ; 212(13): 2203-12, 2015 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-26621454

RESUMO

Psoriasis vulgaris is a common T cell-mediated inflammatory skin disease with a suspected autoimmune pathogenesis. The human leukocyte antigen (HLA) class I allele, HLA-C*06:02, is the main psoriasis risk gene. Epidermal CD8(+) T cells are essential for psoriasis development. Functional implications of HLA-C*06:02 and mechanisms of lesional T cell activation in psoriasis, however, remained elusive. Here we identify melanocytes as skin-specific target cells of an HLA-C*06:02-restricted psoriatic T cell response. We found that a Vα3S1/Vß13S1 T cell receptor (TCR), which we had reconstituted from an epidermal CD8(+) T cell clone of an HLA-C*06:02-positive psoriasis patient specifically recognizes HLA-C*06:02-positive melanocytes. Through peptide library screening, we identified ADAMTS-like protein 5 (ADAMTSL5) as an HLA-C*06:02-presented melanocytic autoantigen of the Vα3S1/Vß13S1 TCR. Consistent with the Vα3S1/Vß13S1-TCR reactivity, we observed numerous CD8(+) T cells in psoriasis lesions attacking melanocytes, the only epidermal cells expressing ADAMTSL5. Furthermore, ADAMTSL5 stimulation induced the psoriasis signature cytokine, IL-17A, in CD8(+) T cells from psoriasis patients only, supporting a role as psoriatic autoantigen. This unbiased analysis of a TCR obtained directly from tissue-infiltrating CD8(+) T cells reveals that in psoriasis HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation. We propose that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway.


Assuntos
Autoantígenos/imunologia , Autoimunidade/imunologia , Melanócitos/metabolismo , Psoríase/imunologia , Proteínas ADAM/metabolismo , Proteínas ADAMTS , Adulto , Sequência de Aminoácidos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Epiderme/metabolismo , Epiderme/patologia , Epitopos/química , Epitopos/imunologia , Feminino , Antígenos HLA-C/imunologia , Humanos , Masculino , Dados de Sequência Molecular , Peptídeos/química , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo
16.
Cell ; 161(4): 919-32, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25957690

RESUMO

Aging has been associated with a progressive decline of proteostasis, but how this process affects proteome composition remains largely unexplored. Here, we profiled more than 5,000 proteins along the lifespan of the nematode C. elegans. We find that one-third of proteins change in abundance at least 2-fold during aging, resulting in a severe proteome imbalance. These changes are reduced in the long-lived daf-2 mutant but are enhanced in the short-lived daf-16 mutant. While ribosomal proteins decline and lose normal stoichiometry, proteasome complexes increase. Proteome imbalance is accompanied by widespread protein aggregation, with abundant proteins that exceed solubility contributing most to aggregate load. Notably, the properties by which proteins are selected for aggregation differ in the daf-2 mutant, and an increased formation of aggregates associated with small heat-shock proteins is observed. We suggest that sequestering proteins into chaperone-enriched aggregates is a protective strategy to slow proteostasis decline during nematode aging.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/metabolismo , Proteoma/metabolismo , Envelhecimento , Animais , Proteínas de Caenorhabditis elegans/genética , Mutação , Agregados Proteicos
17.
Proc Natl Acad Sci U S A ; 111(51): 18219-24, 2014 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-25489109

RESUMO

Expansion of a poly-glutamine (polyQ) repeat in a group of functionally unrelated proteins is the cause of several inherited neurodegenerative disorders, including Huntington's disease. The polyQ length-dependent aggregation and toxicity of these disease proteins can be reproduced in Saccharomyces cerevisiae. This system allowed us to screen for genes that when overexpressed reduce the toxic effects of an N-terminal fragment of mutant huntingtin with 103 Q. Surprisingly, among the identified suppressors were three proteins with Q-rich, prion-like domains (PrDs): glycine threonine serine repeat protein (Gts1p), nuclear polyadenylated RNA-binding protein 3, and minichromosome maintenance protein 1. Overexpression of the PrD of Gts1p, containing an imperfect 28 residue glutamine-alanine repeat, was sufficient for suppression of toxicity. Association with this discontinuous polyQ domain did not prevent 103Q aggregation, but altered the physical properties of the aggregates, most likely early in the assembly pathway, as reflected in their increased SDS solubility. Molecular simulations suggested that Gts1p arrests the aggregation of polyQ molecules at the level of nonfibrillar species, acting as a cap that destabilizes intermediates on path to form large fibrils. Quantitative proteomic analysis of polyQ interactors showed that expression of Gts1p reduced the interaction between polyQ and other prion-like proteins, and enhanced the association of molecular chaperones with the aggregates. These findings demonstrate that short, Q-rich peptides are able to shield the interactive surfaces of toxic forms of polyQ proteins and direct them into nontoxic aggregates.


Assuntos
Peptídeos/metabolismo , Príons/metabolismo , Ligação Proteica , Saccharomyces cerevisiae/genética
18.
Cell ; 156(5): 975-85, 2014 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-24581496

RESUMO

When exposed to proteotoxic environmental conditions, mammalian cells activate the cytosolic stress response in order to restore protein homeostasis. A key feature of this response is the heat shock transcription factor 1 (HSF1)-dependent expression of molecular chaperones. Here, we describe the results of an RNA interference screen in HeLa cells to identify modulators of stress response induction and attenuation. The modulator proteins are localized in multiple cellular compartments, with chromatin modifiers and nuclear protein quality control playing a central regulatory role. We find that the acetyltransferase, EP300, controls the cellular level of activatable HSF1. This involves acetylation of HSF1 at multiple lysines not required for function and results in stabilization of HSF1 against proteasomal turnover. Acetylation of functionally critical lysines during stress serves to fine-tune HSF1 activation. Finally, the nuclear proteasome system functions in attenuating the stress response by degrading activated HSF1 in a manner linked with the clearance of misfolded proteins.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteína p300 Associada a E1A/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Fatores de Transcrição/metabolismo , Acetilação , Animais , Núcleo Celular/metabolismo , Células HEK293 , Células HeLa , Fatores de Transcrição de Choque Térmico , Resposta ao Choque Térmico , Humanos , Dobramento de Proteína , Mapas de Interação de Proteínas , Proteoma/análise , Proteoma/metabolismo
19.
Mol Cell Proteomics ; 11(3): M111.014654, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22167270

RESUMO

Despite the increasing importance of heat shock protein 90 (Hsp90) inhibitors as chemotherapeutic agents in diseases such as cancer, their global effects on the proteome remain largely unknown. Here we use high resolution, quantitative mass spectrometry to map protein expression changes associated with the application of the Hsp90 inhibitor, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG). In depth data obtained from five replicate SILAC experiments enabled accurate quantification of about 6,000 proteins in HeLa cells. As expected, we observed activation of a heat shock response with induced expression of molecular chaperones, which refold misfolded proteins, and proteases, which degrade irreparably damaged polypeptides. Despite the broad range of known Hsp90 substrates, bioinformatics analysis revealed that particular protein classes were preferentially affected. These prominently included proteins involved in the DNA damage response, as well as protein kinases and especially tyrosine kinases. We followed up on this observation with a quantitative phosphoproteomic analysis of about 4,000 sites, which revealed that Hsp90 inhibition leads to much more down- than up-regulation of the phosphoproteome (34% down versus 6% up). This study defines the cellular response to Hsp90 inhibition at the proteome level and sheds light on the mechanisms by which it can be used to target cancer cells.


Assuntos
Benzoquinonas/farmacologia , Dano ao DNA/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Proteínas Tirosina Quinases/metabolismo , Proteoma/metabolismo , Proteômica , Biologia Computacional , Proteínas de Choque Térmico HSP90/metabolismo , Células HeLa , Humanos , Chaperonas Moleculares/metabolismo , Fosfopeptídeos/análise , Fosfopeptídeos/metabolismo , Dobramento de Proteína , Proteoma/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
20.
Cell ; 144(1): 67-78, 2011 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-21215370

RESUMO

Protein aggregation is linked with neurodegeneration and numerous other diseases by mechanisms that are not well understood. Here, we have analyzed the gain-of-function toxicity of artificial ß sheet proteins that were designed to form amyloid-like fibrils. Using quantitative proteomics, we found that the toxicity of these proteins in human cells correlates with the capacity of their aggregates to promote aberrant protein interactions and to deregulate the cytosolic stress response. The endogenous proteins that are sequestered by the aggregates share distinct physicochemical properties: They are relatively large in size and significantly enriched in predicted unstructured regions, features that are strongly linked with multifunctionality. Many of the interacting proteins occupy essential hub positions in cellular protein networks, with key roles in chromatin organization, transcription, translation, maintenance of cell architecture and protein quality control. We suggest that amyloidogenic aggregation targets a metastable subproteome, thereby causing multifactorial toxicity and, eventually, the collapse of essential cellular functions.


Assuntos
Amiloide/metabolismo , Fenômenos Fisiológicos Celulares , Proteínas/metabolismo , Linhagem Celular , Humanos , Complexos Multiproteicos , Dobramento de Proteína , Estrutura Secundária de Proteína , Proteômica
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