Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1073232 | ENA |
REPOSITORIES: ENA
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Project description:14-3-3 proteins are highly conserved regulatory proteins that interact with hundreds of structurally diverse clients and act as central hubs of signaling networks. However, how 14-3-3 paralogs differ in specificity and how they regulate client protein function are not known for most clients. Here, we map the interactomes of all human 14-3-3 paralogs and systematically characterize the effect of disrupting these interactions on client localization. The loss of 14-3-3 binding leads to the coalescence of a large fraction of clients into discrete foci in a client-specific manner, suggesting a central chaperone-like function for 14-3-3 proteins. Congruently, the engraftment of 14-3-3 binding motifs to nonclients can suppress their aggregation or phase separation. Finally, we show that 14-3-3s negatively regulate the localization of the RNA-binding protein SAMD4A to cytoplasmic granules and inhibit its activity as a translational repressor. Our work suggests that 14-3-3s have a more prominent role as chaperone-like molecules than previously thought.
2023-03-06 | GSE201023 | GEO
Project description:14-3-3 proteins are highly conserved regulatory proteins that interact with hundreds of structurally diverse clients and act as central hubs of signaling networks. However, how 14-3-3 paralogs differ in specificity and how they regulate client protein function are not known for most clients. Here, we map the interactomes of all human 14-3-3 paralogs and systematically characterize the effect of disrupting these interactions on client localization. The loss of 14-3-3 binding leads to the coalescence of a large fraction of clients into discrete foci in a client-specific manner, suggesting a central chaperone-like function for 14-3-3 proteins. Congruently, the engraftment of 14-3-3 binding motifs to nonclients can suppress their aggregation or phase separation. Finally, we show that 14-3-3s negatively regulate the localization of the RNA-binding protein SAMD4A to cytoplasmic granules and inhibit its activity as a translational repressor. Our work suggests that 14-3-3s have a more prominent role as chaperone-like molecules than previously thought.
2023-03-06 | GSE201019 | GEO
Project description:Protein tyrosine kinases are involved in regulating growth and proliferation in cells and are often hyperactive in cancerous tissue. Tyrosine kinase inhibitors have been used to limit hyperactivity but become ineffective due to the appearance of resistance mutations. A common trait of hyperactive protein kinases is its strict client relationship with molecular chaperone Hsp90. However, the mechanism behind Hsp90 client kinase recognition is poorly understood. Here we measure the functional effect of thousands of single amino acid variants in the Src kinase domain to identify positions invovled in Hsp90 client recognition.
2023-05-22 | GSE218190 | GEO
Project description:The PAQosome is a large complex composed of the HSP90/R2TP chaperone and a prefoldin-like module. It promotes the biogenesis of cellular machineries but it is unclear how it discriminates closely related client proteins. Among the main PAQosome clients are C/D snoRNPs and in particular their core protein NOP58. Using NOP58 mutants and proteomic experiments, we identify different assembly intermediates and show that C12ORF45, which we rename NOPCHAP1, acts as a bridge between NOP58 and PAQosome. NOPCHAP1 makes direct physical interactions with the CC-NOP domain of NOP58 and domain II of RUVBL1/RUVBL2 AAA+ ATPases. Interestingly, NOPCHAP1 interaction with RuvBL1/2 is disrupted upon ATP binding. Moreover, while it robustly binds both yeast and human NOP58, it makes little interactions with NOP56 and PRPF31, two other closely related CC-NOP proteins. Expression of NOP58, but not NOP56 or PRPF31, is decreased in NOPCHAP1 KO cells. We propose that NOPCHAP1 is a client-loading PAQosome cofactor that selects NOP58 to promote box C/D snoRNP assembly.
2020-12-11 | GSE161155 | GEO
Project description:Identification of mitochondrial client proteins of HSP70 in cancer cells using SILAC and LC-MS/MS.
2020-01-27 | MSV000084845 | MassIVE
Project description:Purpose: Proficient DNA repair by homologous recombination (HR) facilitates resistance to chemo-radiation in glioma stem cells (GSCs). We evaluated whether compromising HR by targeting HSP90, a molecular chaperone required for the function of key HR proteins, using onalespib, a long-acting, brain-penetrant HSP90 inhibitor, would sensitize high-grade gliomas to chemo-radiation in vitro and in vivoExperimental Design: The ability of onalespib to deplete HR client proteins, impair HR repair capacity, and sensitize GBM to chemo-radiation was evaluated in vitro in GSCs, and in vivo using zebrafish and mouse intracranial glioma xenograft models. The effects of HSP90 inhibition on the transcriptome and cytoplasmic proteins was assessed in GSCs and in ex vivo organotypic human glioma slice cultures.Results: Treatment with onalespib depleted CHK1 and RAD51, two key proteins of the HR pathway, and attenuated HR repair, sensitizing GSCs to the combination of radiation and temozolomide (TMZ). HSP90 inhibition reprogrammed the transcriptome of GSCs and broadly altered expression of cytoplasmic proteins including known and novel client proteins relevant to GSCs. The combination of onalespib with radiation and TMZ extended survival in a zebra fish and a mouse xenograft model of GBM compared to the standard of care (radiation and TMZ) or onalespib with radiation.Conclusions: The results of this study demonstrate that targeting HR by HSP90 inhibition sensitizes GSCs to radiation and chemotherapy and extends survival in zebrafish and mouse intracranial models of GBM. These results provide a preclinical rationale for assessment of HSP90 inhibitors in combination with chemoradiation in GBM patients.
2022-04-15 | GSE193635 | GEO
Project description:Here, we present a systematic and quantitative test of the hypothesis that the composition and activities of the endoplasmic reticulum (ER) proteostasis network impact mutational tolerance of secretory pathway client proteins. We focus on influenza hemagluttinin (HA), a viral coat protein that folds in the host’s ER via a complex but well-characterized pathway. By integrating chemical methods to modulate the unfolded protein response with deep mutational scanning to assess mutational tolerance, we discover that upregulation of ER chaperones broadly enhances HA mutational tolerance across numerous sites and secondary/tertiary structure elements, including sites targeted by host antibodies. Remarkably, this host chaperone-enhanced mutational tolerance is observed at the same HA sites where mutational tolerance is most reduced by propagation at a fever-like temperature. Thus, host ER proteostasis mechanisms and temperature modulate HA mutational tolerance in opposite directions. This finding has important implications for influenza evolution, because influenza immune escape is contingent on HA possessing sufficient mutational tolerance to acquire antibody resistance while still maintaining the capacity to fold and function. More broadly, this work provides the first experimental evidence that the composition and activities of the ER proteostasis network critically define the mutational tolerance and, therefore, the evolution of secretory pathway client proteins.
2018-09-10 | GSE115168 | GEO
Project description:We performed targeted transcriptomic analysis on archival biopsies from client-owned dogs to examine immune and skin gene expression profiles in spontaneous canine epitheliotropic lymphoma (EL).
2023-10-26 | GSE213086 | GEO
Project description:We performed targeted transcriptomic analysis on archival biopsies from client-owned dogs to examine immune and skin gene expression profiles in spontaneous canine epitheliotropic lymphoma (EL).
2023-10-26 | GSE211988 | GEO
Project description:We performed a comparative immunology case study of client-owned dogs to determine if immune and skin gene expression profiles in spontaneous canine pemphigus mirror those observed in human pemphigus
2021-09-20 | GSE171079 | GEO