Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The Pathogenic Impact of Cryptic Splicing is Alleviated by Ubiquitination and ER-Phagy

ABSTRACT: RNA splicing and the ubiquitin system allow the functional proteome to adapt in response to changing cellular contexts. However, the regulatory mechanisms connecting these processes remain poorly understood. Here we show that the deregulation of the spliceosome B complex caused by USP39 deficiency leads to a novel splicing profile characterized by the use of cryptic 5′splice sites. Importantly, disruptive variants evade mRNA surveillance pathways and are translated into topologically incorrect proteins. These cryptic isoforms disrupt proteostasis and activate the unfolded protein response, causing ER stress-induced cell death. Human cells respond to this proteotoxicity by enhancing ubiquitin-mediated proteolysis and ER-phagy. Our findings show how cell death triggered by cryptic splicing can be mitigated, and provide insight into the molecular pathogenesis of diseases such as retinitis pigmentosa.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Exploris 480, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Hela Cell

DISEASE(S): Malignant Neoplasm Of Ovary

SUBMITTER: Marina Hoffmann

LAB HEAD: Ivan Dikic

PROVIDER: PXD041509 | Pride | 2024-09-26

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	20201116_MHO_CP_HeLa_Igg_unt_01.raw	Raw
	20201116_MHO_CP_HeLa_Igg_unt_02_201118163254.raw	Raw
	20201116_MHO_CP_HeLa_Igg_unt_03.raw	Raw
	20201116_MHO_CP_HeLa_USP10_unt_01.raw	Raw
	20201116_MHO_CP_HeLa_USP10_unt_02.raw	Raw

Items per page:

1 - 5 of 66

Similar Datasets

GPRC Function in autophagy control: a systematic approach of chemical intervention

Project description:Autophagy facilitates the degradation of cellular content via the lysosome and is involved in cellular homeostasis and stress response pathways. As such, malfunction of autophagy is linked to a variety of diseases ranging from organ specific illnesses like cardiomyopathy to systemic illnesses such as cancer or metabolic syndromes. Given the variety of autophagic functions within a cell and tissue, regulation of autophagy is complex and contains numerous positive and negative feedback loops. While our knowledge of mechanisms for cargo selectivity has significantly improved over the last decade, our understanding of signaling routes activating individual autophagy pathways remains rather sparce. In this resource study, we report on a well-characterized chemical library assembled within the IMI initiative EUbOPEN containing 77 GPCR-targeting ligands that was used to systematically analyze LC3B-based autophagy as well as ER-phagy flux upon compound treatment. The global impact of hit compounds TC-G 1004, BAY 60-6583, PSNCBAM-1, TC-G 1008, LPA2 Antagonist 1, ML154, JTC-801 and ML-290 targeting Adenosine receptor A2a (ADORA2A), Adenosine receptor A2b (ADORA2B), Cannabinoid receptor 1 (CNR1), G-protein coupled receptor 39 (GPR39), Lysophosphatidic acid receptor 2 (LPAR2), neuropeptide S receptor 1 (NPSR1), NOP (OPRL1), and Relaxin receptor 1 (RXFP1) were subsequently analyzed and compared by TMT-based mass spectrometry. Our results indicate the differential impact of targeted GPCRs on known autophagy-associated proteins.

2024-07-18 | PXD047645 | Pride

Discovery of a Small Molecule Degrader that Sustains pan-AKT Degradation and Downstream Signaling Effects

Project description:The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over 50% of tumors showing aberrant AKT hyperactivation. Although potent small molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of GDC-0068, an AKT inhibitor, conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase, Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 hours, even after compound washout. Overall, our findings suggest that AKT degradation may provide prolonged pharmacological effects compared to inhibition, and highlight the potential advantages of AKT-targeted degradation.

2019-11-27 | PXD015207 | Pride

Integrative MHC-I peptidome quantitation with isobaric tagging mass spectrometry

Project description:Despite the appreciation of CD8+ T cell anti-tumor immune responses towards improvement patient outcomes, the MHC-I peptides that facilitate the response are poorly described. Alternatively, whether cancer therapies alter the MHC-I peptide repertoire has not been fully assessed due to the lack of quantitative strategies. In this regard, anthracyclines and ionizing radiation both increase the infiltration of CD8+ T cells into tumors but whether they do so by altering the MHC-I peptidome repertoire is not known. To investigate this, we developed a platform for screening therapy-induced MHC-I peptides by quantitative, multiplexed measurement of MHC-I peptides with tandem mass tags (TMT). We show that both ionizing radiation and the anthracycline doxorubicin induce MHC-I peptides that are largely derived from mitotic progression and cell cycle proteins. Our approach enables further strategies to understand how small molecules and other therapies alter MHC-I peptide presentation that may be harnessed for CD8+ T cell-based immunotherapies.

2019-03-05 | PXD011464 | Pride

Identification and relative quantification of hFSH glycoforms in women sera by PRM MS based approach.

Project description:This study presents an alternative preliminary strategy to identify and quantify serum hFSH glycoforms based on immunopurification assay and mass spectrometry (MS) using parallel reaction monitoring (PRM) analysis. In this study, we provide MS-PRM data acquisition method for hFSH glycopeptides identification with high specificity and their quantification by extracting the chromatographic traces of selected fragments of glycopeptides. Once set up in all its features, the proposed method could be transferred to the clinic to improve the fertility treatments and follow-ups in men and women.

2021-06-15 | PXD025585 | Pride

Plasma and kidney proteome profiling combined with laser capture microdissection reveal large increases in immunoglobulins with age

Project description:One of the main hallmarks of aging is aging-associated inflammation, also known as inflammaging. In this study, by comparing young and old mice using LC-MS profiling, we show that immunoglobulins are the proteins that are most increased with age in plasma. This observation appears to have been previously overlooked as many of the aging proteome profiling experiments to date use targeted antibody/aptamer-based arrays, which typically do not include high abundance proteins or use depletion prior to LC-MS to remove the high abundant proteins. Through LC-MS profiling of young and old mouse kidneys, we also show that immunoglobulins are among the top proteins changing with age. Immunofluorescence staining of kidney sections shows that the main increases in immunoglobulins with age are localized in the glomeruli of the kidney. Using laser capture microdissection coupled with LC-MS, we show an increase in multiple immune related proteins in glomeruli from aged mice. Increased deposition of immunoglobulins and complement proteins in the kidney glomeruli may be a factor leading to reduced filtering capacity of the kidney with age.

2024-07-03 | PXD051031 | Pride

Species identification of silks by protein mass spectrometry

Project description:We investigate a range of methods for solubilizing modern and archaeological silks and demonstrate a protocol using mass spectrometry-based proteomics to successfully differentiate modern samples of Bombyx, Antheraea, and Samia -produced silks matching samples to species level. We also analyzed archaeological silks from excavations at the ancient city of Palmyra, Syria, and provide evidence that these silks were produced by A. mylitta, which is the first direct evidence supporting the production and trade of Indian wild silk in antiquity.

2022-04-04 | PXD024610 | Pride

Species identification of silks by protein mass spectrometry

Project description:Investigating the origins of sericulture is challenging, as classification of silks by species is currently technically difficult. Here we investigate a range of methods for solubilizing modern and archaeological silks and demonstrate a protocol using mass spectrometry-based proteomics to successfully differentiate modern samples of Bombyx, Antheraea, and Samia -produced silks matching samples to species level. We also analyzed archaeological silks from excavations at the ancient city of Palmyra, Syria, and provide evidence that these silks were produced by A. mylitta, which is the first direct evidence supporting the production and trade of Indian wild silk in antiquity.

2022-04-04 | PXD024606 | Pride

Liver-derived plasminogen mediates muscle stem cell expansion during caloric restriction through the plasminogen receptor, Plg-RKT. Bareja, White, Et. Al.

Project description:Quantitative label free proteomic characterization of liver secretomes in mice fed either ona regular or calorie restricted diet.

2024-06-16 | PXD043644 | Pride

"In-gel cross-linking mass spectrometry (IGX-MS) of proteins and protein complexes"

Project description:Cross-linking mass spectrometry has developed into an important method to study protein structures and interactions. The in-solution cross-linking workflows involve time and sample consuming steps and do not provide sensible solutions for differentiating cross-links obtained from co-occurring protein oligomers, complexes, or conformers. Here we developed a cross-linking workflow combining blue native PAGE with in-gel cross-linking mass spectrometry (IGX-MS). This workflow circumvents steps, such as buffer exchange and cross-linker concentration optimization. Additionally, IGX-MS enables the parallel analysis of co-occurring protein complexes using only small amounts of sample. Another benefit of IGX-MS observed by experiments on GroEL and purified bovine heart mitochondria, is the substantial reduction of artificial over-length cross-links when compared to in-solution cross-linking. We next used IGX-MS to investigate the complement components C5, C6, and their hetero-dimeric C5b6 complex. The obtained cross-links were used to generate a refined structural model of the complement component C6, resembling C6 in its inactivated state. This finding shows that IGX-MS can be used to provide new insights into the initial stages of the terminal complement pathway.

2020-12-14 | PXD020014 | Pride

Quantitative proteomics of cells treated with decaged WZB117-PPG

Project description:To further understand how cells response to decaged WZB117-PPG, we performed quantitative proteomics of A549 cells under WZB117-PPG treatment (30 μM) with illumination and normal condition by TMT 10 plex labeling

2024-01-04 | PXD043171 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data