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Cubilin is a Novel Target Antigen in Anti-Brush Border Antibody Disease

ABSTRACT: Autoimmune diseases that affect the kidney proximal tubule (PT) cause proteinuria and are implicated in the pathogenesis of kidney failure. Previous evidence demonstrated that circulating anti-brush border antibodies (ABBA) target megalin (LRP2) but whether other components of the PT drive autoimmunity was unknown. Here we investigate a patient with LRP2-negative ABBA disease, and applied immunoprecipitation, mass spectrometry, and confocal imaging to identify cubilin as a novel antigen associated with the autoimmune disorder.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Proximal Tubule, Kidney

SUBMITTER: Aaron Storey

LAB HEAD: Christopher Larsen

PROVIDER: PXD030159 | Pride | 2023-04-06

REPOSITORIES: Pride

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			Action	DRS
	Arkana_032521_Sample_02.dia	Other
	Arkana_032521_Sample_02.dia.elib	Other
	Arkana_032521_Sample_02.mzML	Mzml
	Arkana_032521_Sample_03.dia	Other
	Arkana_032521_Sample_03.dia.elib	Other

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Publications

Cubilin and amnionless protein are novel target antigens in anti-brush border antibody disease.

Morelle Johann J Caza Tiffany T Debiec Hanna H Aydin Selda S Storey Aaron A Ronco Pierre P Larsen Christopher C

Kidney international 20220308 5

PMID: 35276203

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Minor Antigens in Membranous Nephropathy Identified by Mass Spectrometry

Project description:Background: Multiple autoantigens have been identified in membranous nephropathy (MN) by tissue-based proteomics. However, the antigenic targets of disease are unknown for >10% of MN and >50% of membranous lupus nephritis (MLN) cases. We identified multiple new targets in PLA2R-/THSD7A-/EXT-/NELL1-quadruple negative MN biopsies through mass spectrometry (MS) of immune complexes recovered from biopsy tissue of patients with MN. Methods: MN cases negative for PLA2R, THSD7A, EXT1/2, and NELL1 were identified from a biopsy database. Protein G immunoprecipitation was used to recover immune complexes from frozen biopsy tissue, followed by interrogation by mass spectrometry (MS). Potential antigens were confirmed through paraffin immunofluorescence of protein targets, followed by co-localization with IgG within immune deposits. Consecutive series of 165 cases of PLA2R-negative MN biopsies and 95 MLN biopsies was screened to determine the frequency for each potential antigen. Results: Seven protein targets were discovered within immune complexes from MN biopsies including FCN3, CD206, EEA1, SEZ6L2, NPR3, MST1, and VASN. Peptides from these proteins on MS were not enriched in PLA2R (n=86), THSD7A (n=64), NELL1 (n=64), or EXT1/2 (n=60) controls. Between 3-30 unique peptides were detected for each target. Frequencies of each antigen, determined by staining consecutive case series, were SEZ6L2 (1/165 idiopathic; 0/95 MLN), VASN (8/165 idiopathic; 2/95 MLN), EEA1 (6/165 idiopathic; 7/95 MLN), MST1 (6/165 idiopathic; 2/95 MLN), and FCN3 (0/165 idiopathic, 6/95 MLN), NPR3 and CD206 were positive in index cases. All cases showed co-localization of IgG within immune deposits. Conclusion: Seven novel protein targets were identified in MN and MLN.

2023-04-06 | PXD035853 | Pride

Cellular, molecular and proteomic characteristics of early Hepatocellular carcinoma

Project description:Ηepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Early de-tection/diagnosis is vital for the prognosis of HCC whereas diagnosis at late stages is associated with very low survival rate. Early diagnosis is based on patient’s 6 month surveillance and use of at least two imaging modalities. The aim of this study was to investigate diagnostic markers for the detection of early HCC based on proteome analysis, microRNAs (miRNAs) and circulat-ing tumor cells (CTCs) in the blood of patients with cirrhosis, early and advanced HCC. We studied 89 patients with HCC of whom 33 had early HCC and 28 cirrhotic patients. CTCs were detected by Real-Time Quantitative Reverse Transcription PCR and immunofluorescence using the markers Epithelial cell adhesion molecule (EPCAM), Vimentin, A Fetoprotein (AFP) and surface major Vault protein (sMVP). Expression of the five most commonly HCC-involved miRNAs (miR-122, miR-200a, miR-200b, miR-221, miR-222) was examined in the serum by qRT-PCR. Finally patient serum was analyzed by whole proteome analysis (LC/MS). Twenty seven out of 53 (51%) patients with advanced HCC had detectable CTCs. Among them, 10/27 (37%) presented evidence of mesenchymal or intermediate stage cells (vimentin and/or sMVP positive). Moreover, 5/17 (29%) patients with early HCC and 6/28 (21%) cirrhotic patients had detectable CTCs. Patients with early and advanced HCC exhibited a significant increase of miR-200b when compared to cirrhotic patients. Our proteome analysis indicated that early HCC patients present a significant upregulation of APOA2, APOC3 proteins when compared to cir-rhotic patients, that when used in combination, cover the 100% of the patients with early HCC. In conclusion, miR-200b, APOA2 and APOC3 proteins are sensitive markers and can be poten-tially useful in combination for the early diagnosis of HCC.

2023-03-11 | PXD033306 | Pride

Maternal hyperglycemia induces alterations in hepatic amino acid, glucose and lipid metabolism of neonatal offspring: Multi-omics insights from a diabetic pig model

Project description:Intrauterine exposure to disturbed maternal glucose metabolism is associated with adverse consequences for the offspring. Hepatic disorders in affected offspring emerge in early development; thus, detection of disease biomarkers at an early stage may elucidate the underlying mechanisms of maternal hyperglycemia-induced metabolic disease and improve timely diagnosis and treatment strategies. To systematically study the molecular consequences of maternal hyperglycemia, we used data independent acquisition (DIA) proteomics and compared the molecular profiles of liver of three days old wild-type piglets born to a transgenic hyperglycemic pig model with those of wild-type piglets born to normoglycemic mothers.

2023-07-10 | PXD040305 | Pride

Proteomics Indicates Lactate Dehydrogenase is Prognostic in Acetaminophen-induced Acute Liver Failure Patients and Reveals a Role for LKB1-AMPK Signaling

Project description:Better biomarkers to predict death early in acute liver failure (ALF) are needed. To that end, we obtained early (study day 1) and later (day 3) serum samples from transplant-free survivors (n=28) and non-survivors (n=30) of acetaminophen (APAP)-induced ALF from the NIH-sponsored Acute Liver Failure Study Group, and from control volunteers (n=10). To identify proteins that increase early in serum during ALF, we selected individuals from this cohort for whom ALT was lower on day 1 than day 3, indicating a time point before the peak of injury (n=10/group). We then performed untargeted proteomics on their day 1 samples. Out of 1,682 quantifiable proteins, 79 were elevated ≥4-fold in ALF patients vs. controls and 23 of those were further elevated ≥4-fold in non-survivors vs. survivors, indicating potential to predict death. Interestingly, the biomarker with best performance was LDH. To confirm the prognostic potential of LDH, we measured activity in all day 1 and 3 samples from all 58 ALF patients. LDH was elevated in the non-survivors vs. survivors on both days. In addition, receiver operating characteristic (ROC) curve analyses revealed that LDH alone performed similarly to the model for end-stage liver disease (MELD), while a combination of MELD and LDH outperformed either alone. Finally, Upstream Analysis of our proteomics data indicated activation of LKB1-AMPK signaling in liver regeneration after APAP overdose and we confirmed that in mice. Overall, we conclude LDH can predict death in APAP-induced ALF and that LKB1-AMPK signaling may be a promising therapeutic target to improve survival.

2022-08-12 | PXD029576 | Pride

Syntaxin5’s flexibility in SNARE pairing supports Golgi functions

Project description:The intracellular transport system is an evolutionally conserved, essential, and highly regulated network of organelles and small transport carriers that traffic protein and lipid cargoes within the cell. The Conserved Oligomeric Golgi (COG) complex is the major Golgi Multisubunit Tethering Complex. Its key function is orchestration of SNARE mediated fusion of cargo carriers at the Golgi. We hypothesized the depletion of the major Golgi SNAREs GS28 (GOSR1) and GS15 (BET1L) due to COG malfunction is the major contributor to COG-related glycosylation defects. To test this, we created single, double and triple knockouts (KO) of Golgi SNAREs in HEK293T cells and analyzed the resulting mutants using a comprehensive set of biochemical, mass-spectrometry (MS) and microscopy approaches. Deletion of GS28 significantly affected GS15, but not the other two partners, STX5 and YKT6. Surprisingly, our analysis revealed that COG dysfunction is more deleterious for Golgi function than disrupting the canonical Golgi SNARE complex indicating the existence of an adaption mechanism. Indeed, quantitative mass-spectrometry analysis of STX5-interacting proteins revealed unexpected flexibility in Golgi SNARE pairing in mammalian cells. We uncovered two novel non-canonical Golgi SNARE complexes – STX5/SNAP29/VAMP7 and STX5/VTI1B/GS15/YKT6 which were increased in GS28 KO cells. Upon GS28 deletion, SNAP29 remarkably localized to the Golgi. Merely mislocalizing STX5 from Golgi abolished the SNARE substitution causing dramatic glycosylation defects. Our data points to the remarkable plasticity in the intra-Golgi membrane fusion machinery and places STX5 as the only essential Golgi Qa-SNARE.

2023-06-26 | PXD036741 | Pride

DLST mutations in pheochromocytoma and paraganglioma cause proteome hyposuccinylation and metabolic remodeling

Project description:Using stable cell lines, we found that succinylation levels were highly dependent on DLST. Furthermore, PPGL-causing DLST mutations, predicted to alter DLST homo-oligomeric complex structure, caused a significant remodeling of the cellular succinylome. Succinylation is thought to cause major chemical and structural changes in proteins, most likely influencing their function. Accordingly, we found that the dysregulation of succinylation appeared to influence several essential pathways related to PPGL development such as hypoxia, glycolysis and oxidative phosphorylation. This study points to succinylation as a new mechanism involved in the development of PPGLs, supporting the growing body of research highlighting the role of this PTM in different types of cancer.

2023-05-04 | PXD036782 | Pride

The regulatory landscape of the yeast phosphoproteome – quantitative proteomics DIA data

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2023-08-27 | PXD034997 | Pride

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2023-08-27 | PXD035050 | Pride

Multi-omics profiling of lung samples from genetically diabetic pigs reveals reduced ALOX15 expression and impaired eicosanoid switching as mechanisms contributing to a proinflammatory milieu

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2024-07-01 | PXD038014 | Pride

Organism-wide secretome mapping of tissue crosstalk in exercise

Project description:Physical activity is a powerful physiologic stimulus that provides benefits to multiple organ systems and confers protection against disease. These physiologic effects are in part mediated by blood-borne factors that mediate tissue crosstalk and function as molecular effectors of physical activity. To globally understand how physical activity reshapes cellular secretomes, here we applied a proximity biotinylation approach to profile cell type-specific secretomes from blood plasma following treadmill running in mice. This organism-wide, 21-cell type, 10-tissue in-vivo secretome atlas reveals complex cell type-specific and bidirectional modulation of secreted proteins across all cell types following exercise training. We identify a gradient of secretome responses across cell types, with secretomes from Pdgfra+ being one of the most exercise-responsive in the entire dataset. Peptide-level correlation analysis revealed widespread and cell type-specific exercise regulation of secreted proteoforms. Finally, we show that exercise-inducible secretion of soluble CES2 proteins from the liver suppresses obesity in high fat diet-fed mouse models. Together, these data identify specific exercise-regulated cell types and secreted proteins and illuminate the dynamic remodeling of cell and tissue crosstalk by physical activity.

2023-07-21 | PXD034535 | Pride

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