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Target search for self-reactive antibodies in human renal allograft rejection

ABSTRACT: Self-reactive antibodies cloned from B cells infiltrating in a human renal allograft were subjected to IP-mass spectrometry using nuclear lysates of HEp-2 cells.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Donald Wolfgeher

LAB HEAD: Dr. Marcus R. Clark

PROVIDER: PXD022989 | Pride | 2021-04-27

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	190305_SPROT_Human_Iso_UP5640.fasta	Fasta
	190604_YA2_Index.txt	Txt
	190604_YA2_MQ1FDR.xml	Xml
	190605_YA2_MQ1FDR.sf3	Other
	190916_SPROT_Human_Iso_UP5640.fasta	Fasta

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1 - 5 of 78

Publications

Innate-like self-reactive B cells infiltrate human renal allografts during transplant rejection.

Asano Yuta Y Daccache Joe J Jain Dharmendra D Ko Kichul K Kinloch Andrew A Veselits Margaret M Wolfgeher Donald D Chang Anthony A Josephson Michelle M Cunningham Patrick P Tambur Anat A Khan Aly A AA Pillai Shiv S Chong Anita S AS Clark Marcus R MR

Nature communications 20210716 1

Intrarenal B cells in human renal allografts indicate transplant recipients with a poor prognosis, but how these cells contribute to rejection is unclear. Here we show using single-cell RNA sequencing that intrarenal class-switched B cells have an innate cell transcriptional state resembling mouse peritoneal B1 or B-innate (Bin) cells. Antibodies generated by Bin cells do not bind donor-specific antigens nor are they enriched for reactivity to ubiquitously expressed self-antigens. Rather, Bin ce ...[more]

PMID: 34272370

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Comparative interactome analysis of Nematostella vectensis Hsp70 isoforms reveals unique clientome remodeling upon heat stress.

Project description:Comparative interactome analysis of Nematostella vectensis Hsp70 isoforms reveals unique clientome remodeling upon heat stress. Three isoforms of nvHSP70 (A, B, and D) were IP'd from either Heat Shock conditions (HS) or non-Heat Shock (UN) and their interactomes were compared. Mass Spec was run on a Q-Exactive (Orbitrap).

2019-06-25 | PXD012144 | Pride

Biomarkers of pediatric cataracts: a proteomics analysis of aqueous fluid

Project description:Abstract Background: Cataracts are among the most common causes of childhood vision loss worldwide. This study seeks to identify differentially expressed proteins in the aqueous humor of pediatric cataract patients. Methods: Samples of aqueous humor were collected from pediatric and adult cataract patients and underwent mass spectrometry-based proteomic analysis. Samples of pediatric cataracts were grouped by subtype and compared to adult samples. Differentially expressed proteins in each subtype were identified. Gene ontology analysis was performed using WikiPaths for each cataract subtype. Results: Seven pediatric patients and ten adult patients were included in the study. Of the pediatric samples, all seven (100%) were male, three (43%) had traumatic cataracts, two (29%) had congenital cataracts, and two (29%) had posterior polar cataracts. Of the adult patients, seven (70%) were female and seven (70%) had predominantly nuclear sclerotic cataracts. 128 proteins were upregulated in the pediatric samples and 127 proteins were upregulated in the adult samples, with 75 proteins shared by both groups. Gene ontology analysis identified inflammatory and oxidative stress pathways as upregulated in pediatric cataracts. Conclusions: Inflammatory and oxidative stress mechanisms may be involved in pediatric cataract formation and warrant further investigation.

2023-07-20 | PXD022529 | Pride

Mevalonate pathway activity is a key determinant of radiation sensitivity in head and neck cancer

Project description:Radioresistance is a major hurdle in the treatment of head and neck squamous cell carcinoma (HNSCC). Here we report a novel role for statin-based treatment of HNSCCs as an actionable and safe adjuvant to radiotherapy. Proteomic profiling and comparison of radiosensitive and radioresistant HNSCCs revealed differential regulation of the mevalonate biosynthetic pathway. Consistent with this finding, inhibition of the mevalonate pathway by pitavastatin (and other related statins) sensitized SQ20B cells to ionizing radiation (IR) and reduced their clonogenic potential. In an effort to uncover the mechanism behind this statin-mediated sensitization, we analyzed prenylation of several important cellular targets upon combined IR-statin treatment. Overall, this study reinforces the view that the mevalonate pathway is a promsing novel therapeutic target in radioresistant HSNCCs.

2019-06-25 | PXD007188 | Pride

Chemotherapy-induced cellular senescence is characterized by aberrant lipid regulation and lipid peroxidation

Project description:As normal cells approach their proliferative limit, they arrest to undergo replicative senescence, displaying large cell size, flat morphology and activation of senescence-associated beta-galactosidase (SA-b-Gal). A subset of normal or tumor cells exposed in vitro or in vivo to chemotherapy agents such as etoposide perform a related response with a similar cellular phenotype dubbed therapy-induced senescence (TIS). High cellular heterogeneity in samples including TIS cells can impede confident determination of senescence-specific factors, frustrating discovery of markers and targets for functional analysis. As a TIS study model, we treated murine melanoma cells with the chemotherapeutic etoposide, applied a live-cell fluorescent SA-b-Gal senescence assay, and utilized fluorescence-activated cell sorting (FACS) to enrich TIS cells. Enriched senescent cell samples were subjected to mass spectrometry and label-free quantitative proteomics analysis, alongside proliferating and quiescent cell samples. Systems biology analysis revealed that senescent cells overexpress proteins and pathways regulating glycolipid processing, lipid metabolism, and lipid peroxidation. Senescence-associated activation of numerous glycosidases was observed, along with elevated cell surface expression of several major lipid regulatory proteins. Senescent cells were found to contain abundant lipid droplets and to import various types of extracellular lipids in correlation with extent of SA-b-Gal expression, and tumor cells were observed to spontaneously senesce in the presence of excess ceramide or triglycerides. Redox-induced lipid peroxidation, resulting in accumulation of cellular reactive aldehydes and consequent expression of aldehyde detoxification enzymes, was observed to be a key feature of TIS induced by three DNA-damaging chemotherapeutics.

2017-11-06 | PXD006216 | Pride

Post-Translational Modifications of recombinant Hsp70s expressed in different systems can alter their functional properties

Project description:Post-Translational Modifications of recombinant Hsp70s expressed in different systems can alter their functional properties

2020-03-13 | PXD011583 | Pride

Rapid acetylation of yeast Hsp70 mediates the cellular response to heat stress

Project description:Hsp70 is a highly conserved molecular chaperone critical for the folding of new and denatured proteins. While traditional models state that cells respond to stress by upregulating inducible HSPs, this response is relatively slow and is limited by transcriptional and translational machinery. Recent studies have identified a number of post-translational modifications (PTMs) on Hsp70 that act to fine-tune its function. We utilized mass spectrometry to determine whether yeast Hsp70 (Ssa1) is differentially modified upon heat shock. We uncovered four lysine residues on Ssa1, K86, K185, K354 and K562 that are deacetylated in response to heat shock. Mutation of these sites cause a substantial remodeling of the Hsp70 interaction network of co-chaperone partners and client proteins while preserving essential chaperone function. Acetylation/deacetylation at these residues alter expression of other heat-shock induced chaperones as well as directly influencing Hsf1 activity. Taken together our data suggest that cells may have the ability to respond to heat stress quickly though Hsp70 deacetylation, followed by a slower, more traditional transcriptional response.

2020-02-24 | PXD015185 | Pride

O-GlcNAcylation enhances double strand break repair, promotes cancer cell proliferation and prevents therapy-induced senescence in irradiated tumors

Project description:The metabolic reprogramming associated with characteristic increases in glucose and glutamine metabolism common in advanced cancer is often ascribed to answering a higher demand for metabolic intermediates required for rapid tumor cell growth. Instead, recent discoveries have pointed to an alternative role for glucose and glutamine metabolites as cofactors for chromatin modifiers and other protein post-translational modification enzymes in cancer cells. Beyond epigenetic mechanisms regulating gene expression, many chromatin modifiers also modulate DNA repair, raising the question whether cancer metabolic reprogramming may mediate resistance to genotoxic therapy and genomic instability. Our prior work had implicated N-acetyl-glucosamine (GlcNAc) formation by the hexosamine biosynthetic pathway (HBP) and resulting protein O-GlcNAcylation as a common means by which increased glucose and glutamine metabolism can drive double strand break (DSB) repair and resistance to therapy-induced senescence in cancer cells. Here, we have examined the effects of modulating O-GlcNAcylationon the DNA damage response in MCF7 human mammary carcinoma xenograft tumors. Promotingprotein O-GlcNAc modification, whether by targeting O-GlcNAcase (OGA) with shRNA or the inhibitor PUGNAc or simply treating animals with GlcNAc, protected tumor xenografts against radiation. In turn, suppressing protein O-GlcNAcylation by silencing O-GlcNActransferase (OGT) or treating animals with alloxan led to delayed DSB repair, reduced cell proliferation, and increased cell senescence in vivo. Taken together, these findings confirm critical connections between cancer metabolic reprogramming, DNA damage response, and senescence and provide a rationale to evaluate agents targeting O-GlcNAcylation in patients as a means to restore tumor sensitivity to radiotherapy.

2019-04-30 | PXD010820 | Pride

A Novel Method for Isolating Whole Protein from Human Cranial Bone

Project description:The presence of the extracellular matrix within human bone limits the applicability of conventional protocols for protein extraction. As a result, complete and accurate characterization of human bone proteome is yet to be performed, and as a result, several bone-related diseases such as craniosynostosis and osteosarcoma are still poorly understood. We sought to develop a reproducible method for extracting whole proteins of varying molecular weights from human cranial bone. Whole protein was extracted from human cranial suture by mechanically processing samples using a method that minimized heat introduction to proteins to limit degradation. Western blotting suggests the presence of whole protein while mass spectrometry was used to sequence peptides and identify isolated proteins. Molecular weights of extracted protein ranged from 9.4-629 kDa and contained proteins of both intra- and extra-cellular origin. High correlation scores among suture protein spectral counts suggest the reproducibility of the method. Ontology analytics revealed proteins of myriad functions including mediators of metabolic processes and cell organelles. These results suggest a reproducible method for isolation of whole protein representing a large range of molecular weights, origins and functions.

2016-10-05 | PXD003215 | Pride

Mps1 Phosphorylation of the Molecular Chaperone Hsp90 Regulates Mitotic Checkpoint

Project description:SUMMARY Mps1 protein kinase is required for accurate chromosome segregation during the mitotic checkpoint. The molecular chaperone Heat Shock Protein 90 (Hsp90) has been linked to Mps1 activity, however the molecular mechanismsunderlying this regulatory process remain elusive. We report that Mps1 directly phosphorylates a conserved threonine residue (T101 in yeast Hsp90 and T115 in human Hsp90) in the N domain of Hsp90. This phosphorylation regulates chaperone function by reducingHsp90 ATPase activity andfosteringits association with kinase client proteins including Mps1. Phosphorylation of T101is also essential for the mitotic checkpoint because it confers Mps1 stability and activity.Additionally,Mps1 phosphorylation of Hsp90 sensitizes cells to Hsp90 inhibitors and elevated Mps1 levels confer tumor selectivity on Hsp90 drugs.Finally,we identified Cdc14 as the phosphatasethat dephosphorylatesT101 and disruptsthe Mps1-Hsp90 interaction. This leads to degradation of Mps1,thusproviding a mechanism for its inactivation and mitotic exit.

2016-01-27 | PXD001969 | Pride

c-Abl Dependent Tyrosine Phosphorylation of theCo-chaperone Aha1 Regulates Interaction with Hsp90

Project description:The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity tailoring the chaperone function to specific “client” proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Hsp90 remain unknown. Here we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1) promoting its interaction with Hsp90. This also increases Hsp90 ATPase activity,enhancesHsp90 interaction with kinase clients,and compromises the chaperoning of non-kinase clients such as glucocorticoid receptor and CFTR. Suggesting a new regulatory paradigm, we find that Y223 phosphorylation leads to ubiquitination and degradation of hAha1 in the proteasome. Finally pharmacologic inhibition of c-Abl prevents hAha1 interaction with Hsp90 thereby, hypersensitizing cancer cells to Hsp90 inhibitors bothin vitro and ex vivo.

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