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Impact of PPP1R1A Knockdown on the Proteomic Landscape of INS-1 Cells: A Focus on Significant Modulated Pathways
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Orientador(es)
Resumo(s)
PPP1R1A (protein phosphatase 1 regulatory inhibitor subunit 1A) is a cAMP/PKA-responsive inhibitor of protein phosphatase 1 (PP1) with a pivotal role in pancreatic β-cell physiology. To investigate its functional impact, Ppp1r1a was silenced in INS-1 (832/13) rat β-cells, and proteomic alterations were profiled using label-free DIA mass spectrometry (Orbitrap Exploris 480) with a rat spectral library. Quantitative analysis (n = 4/group) identified ∼2846 proteins with >2-fold change, revealing extensive proteome reprogramming. Key biological processes affected included vesicle trafficking and exocytosis, insulin biosynthesis and processing, organelle organization, mRNA processing, and autophagy. Pathway enrichment highlighted disruptions in insulin secretion, insulin resistance, and mTOR signaling. Crucial β-cell proteins, including INS2, Cacna1a, CPEB2, PCSK2, SNAP25, SYT5, and VAMP7, were significantly downregulated. Validation confirmed reduced phosphorylated AKT levels and p-AKT/T-AKT ratio, consistent with impaired mTOR signaling. Collectively, these findings demonstrate that PPP1R1A is essential for maintaining β-cell function and insulin secretion, and its depletion triggers broad proteomic and signaling alterations. Thus, PPP1R1A emerges as a regulatory node with potential therapeutic relevance in modulating β-cell activity and insulin dynamics in diabetes.
Descrição
Palavras-chave
AKT Phosphorylation PPP1R1A Insulin Secretion mTOR Signaling Pancreatic β-cells Proteomics Genómica Funcional e Estrutural
Contexto Educativo
Citação
J Proteome Res. 2026 Jan 2;25(1):460-470. doi: 10.1021/acs.jproteome.5c00889. Epub 2025 Dec 8.
Editora
American Chemical Society