Dataset Information

Global Phosphoproteomics Reveals Molecular Networks in Systemic Lupus Erythematosus

ABSTRACT: Systemic lupus erythematosus (SLE) is a systemic and heterogeneous autoimmune disease for which its treatment and phosphorylation-dependent regulatory mechanism remain elusive. Here, we aim to explore the molecular mechanism of phosphorylation regulation for SLE. We employed high-throughput Phosphoproteomics of peripheral blood mononuclear cells (PBMCs) from 126 patients with SLE remission stage (SLE_S), 70 patients with SLE active stage (SLE_A), 160 patients with RA, and 135 healthy controls (HC). An independent cohort that included 60 SLE_S, 35 SLE_A, 50 RA and 40 HC was used to validate the phosphosites via parallel reaction monitoring (PRM). We revealed upregulated pathways involved in cell adhesion and migration in patients with SLE (SLE_S and SLE_A) compared with HCs and RA. Expression pattern clustering analysis revealed several specifically upregulated phosphosites, and the leukocyte transendothelial migration was specifically enriched in SLE_A. We predicted several key kinases including MAP3Ks, MAP2Ks, IKKB and TBK1, and found that upregulated kinase activity is associated with increased phosphorylation of VCL, TLN1 and VAPB by kinases-substrate network analysis. These phosphorylated proteins also regulate the pathways related to cell adhesion and migration, and which have not been implicated in previous studies of SLE. Moreover, we validated these phosphosites with the same trend as 4D-LFQ data, including LCP1 S5, TLN1 S1201, TLN1 S1225, VCL S275 and VCL S579. In summary, the present study elucidates the changes of phosphosites, kinases and pathways in SLE, and may provide potentially novel targets for further mechanism exploration.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Peripheral Blood Mononuclear Cell

SUBMITTER: Shuhui Meng

LAB HEAD: Shuhui Meng

PROVIDER: PXD025399 | Pride | 2023-03-11

REPOSITORIES: Pride

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Global Phosphoproteomics Unveils Kinase-Regulated Networks in Systemic Lupus Erythematosus.

Meng Shuhui S Li Teng T Wang Tingting T Li Dandan D Chen Jieping J Li Heng H Cai Wanxia W Zeng Zhipeng Z Liu Dongzhou D Tang Donge D Hong Xiaoping X Dai Yong Y

Molecular & cellular proteomics : MCP 20221027 12

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by immune complex deposition in multiple organs. Despite the severe symptoms caused by it, the underlying mechanisms of SLE, especially phosphorylation-dependent regulatory networks remain elusive. Herein, by combining high-throughput phosphoproteomics with bioinformatics approaches, we established the global phosphoproteome landscape of the peripheral blood mononuclear cells from a large number of SLE patients, including ...[more]

PMID: 36309313

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Project description:Phosphorylation is a widespread post-translational modification that regulates numerous biological processes. Viruses can alter the physiological activities of host cells to promote virus particle replication, and manipulating phosphorylation is one of the mechanisms. Senecavirus A (SVA) the causative agent of porcine idiopathic vesicular disease. Although numerous studies on SVA have been performed, comprehensive phosphoproteomics analysis of SVA infection is lacking. In the present study, we performed a quantitative mass spectrometry-based phosphoproteomics survey of SVA infection in instituto biologico-rim suino-2 (IBRS-2) cells. Three parallel experiments were performed and 4520 phosphosites were identified on 2084 proteins. Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses showed that many of the phosphorylated proteins were involved in apoptosis and spliceosome pathways, and subcellular structure localisation analysis revealed that more than half were located in the nucleus. Motif analysis of proteins with differentially regulated phosphosites showed that proline, aspartic acid and glutamic acid were the most abundant residues in the serine motif, while proline and arginine were the most abundant in the threonine motif. Forty phosphosites on 27 proteins were validated by parallel reaction monitoring phosphoproteomics, and 30 phosphosites in 21 proteins were verified. Nine proteins with significantly altered phosphosites were further explored, and eight (SRRM2, CDK13, DDX20, DDX21, BAD, ELAVL1, PBK, and STAT3) may play a role in SVA infection. Finally, identified eight predicted kinases, and the kinase activity of inhibitor of nuclear factor kappa-B kinase subunit β and CDK9 was reversed following SVA infection. This is the first phosphoproteomics analysis of SVA infection of IBRS-2 cells, and the results greatly expand our knowledge of SVA infection. The findings provide a basis for studying the interactions of other picornaviruses and their mammalian host cells.

Dataset Information

Global Phosphoproteomics Reveals Molecular Networks in Systemic Lupus Erythematosus

Publications

Global Phosphoproteomics Unveils Kinase-Regulated Networks in Systemic Lupus Erythematosus.

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