ArticleRheumatology (Oxford, England)2026
Structural alterations in PPP1R13L, SAE1, ATP5A1 and PCK2 disrupt NF-κB signalling and mitochondrial metabolism in primary dermal fibroblasts in systemic sclerosis.
Article in Rheumatology (Oxford, England), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveSSc is a proteopathy with limited diagnostic and therapeutic options. This study aimed to uncover structural protein alterations in dermal fibroblasts from diffuse cutaneous (dc)SSc patients using a novel method: limited proteolysis-MS (LiP-MS).
methodsUntreated primary dermal dcSSc fibroblasts and healthy control (HC) fibroblasts were analysed by LiP-MS to detect proteome-wide conformational changes. Fibroblasts were further stimulated with inflammatory cytokines: TNFα, IL-1β, TGF-β and IL-17A, highly relevant in SSc. NF-κB activity was assessed via luciferase reporter assays, while immunoblotting measured total and phosphorylated p65. ATP levels were quantified with luminescent assays, and caspase-3/7 activity was used to assess apoptosis.
resultsLiP-MS identified 53 263 peptides corresponding to 5310 proteins, of which 41 showed significant conformational differences in SSc fibroblasts compared with HCs. Four proteins mapped to NF-κB signalling, while eight were linked to metabolism. Notably, structural changes were detected near functional domains of PPP1R13L and SAE1 (NF-κB regulators) and in ATP5A1 and PCK2 (mitochondrial metabolism). Functional analyses showed that TGF-β stimulation modulated NF-κB activity and the phospho-p65/total-p65 ratio, while IL-17A stimulation induced more pronounced ATP alterations in SSc fibroblasts compared with HCs.
conclusionNovel method LiP-MS successfully revealed protein conformational changes in SSc fibroblasts, particularly in domains central to NF-κB signalling and metabolic regulation. LiP-MS represents a powerful proteome-wide strategy for mapping protein structural perturbations and identifying candidate proteins and pathways for future mechanistic investigation, thereby offering a unique opportunity to connect protein conformational changes with cellular dysfunction and to potentially guide precision therapeutic approaches in SSc.
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