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QPCT-PDIA4 rescues ΔF508 and N1303K CFTR function in cystic fibrosis

ABSTRACT: Cystic fibrosis (CF) is a genetic disorder caused by CFTR mutations, most commonly ΔF508, leading to defective ion transport and multisystem pathology. Small-molecule modulators partially restore mutant CFTR function, but therapeutic efficacy remains limited, particularly for N1303K mutation refractory to current treatments. Here, we show that inhibition of the glutaminyl-peptide cyclotransferase (QPCT)-dependent pathway rescues both the surface expression and functional activity of ΔF508 CFTR. Integrated molecular and physiological analyses identify protein disulfide-isomerase A4 (PDIA4) as a key mediator of this rescue via its pyroglutamate (pGlu)-dependent interaction with ΔF508 CFTR, which is essential for surface trafficking. Furthermore, inhibition of QPCT also restores the function of the N1303K CFTR mutant, revealing a broader mechanistic relevance of this pathway in correcting CFTR misfolding and trafficking defects. These findings uncover a generalizable mechanism for correcting CFTR folding abnormalities and suggest new therapeutic strategies for mutations unresponsive to existing modulators.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Cystic Fibrosis

SUBMITTER: Le Sun

LAB HEAD: John Yates

PROVIDER: PXD069857 | Pride | 2026-06-05

REPOSITORIES: Pride

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			Action	DRS
	20250419_PDIA4_IP_shCTR_1.raw	Raw
	20250419_PDIA4_IP_shCTR_2.raw	Raw
	20250419_PDIA4_IP_shCTR_3.raw	Raw
	20250419_PDIA4_IP_shQPCT_1.raw	Raw
	20250419_PDIA4_IP_shQPCT_2.raw	Raw

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Project description:Background: CFTR modulators will decrease some etiologies of inflammation in the CF airway; however, current data indicate that non-resolving airway infection and inflammation will persist in individuals with CF and chronic bacterial infections. Thus, identification of therapies that diminish CF airway inflammation without allowing unrestrained bacterial growth remains a critical research goal. Novel strategies for combatting deleterious airway inflammation require a better understanding of the cellular contributions to chronic CF airway disease, and how cells change after initiation of CFTR modulator therapy. Peripheral blood monocytes, which traffic to the CF airway, can develop both pro-inflammatory and inflammation-resolving phenotypes, and represent intriguing targets for focused therapies to dampen CF airway inflammation. Material and Methods: In order to characterize the inflammatory phenotype of CF blood monocytes, and how these cells change after initiation of CFTR modulator therapy, we studied adults (n=10) with CF, chronic airway infections, and the CFTR-R117H mutations before and 7 days after initiation of ivacaftor. Transcriptomes of freshly isolated blood monocytes were interrogated by RNA-sequencing (RNA-seq). Plasma concentrations of cytokines and chemokines were evaluated by multiplex ELISA. Results: RNAseq identified approximately 50 monocyte genes for which basal expression was significantly changed in all 10 subjects after 7 days of ivacaftor. Of these, the majority were increased in expression post ivacaftor, including many genes traditionally associated with enhanced inflammation and immune responses. Pathway analyses confirmed that transcriptional pathways were overwhelmingly up-regulated in monocytes after 7 days of ivacaftor, including transcriptional modules associated with immunity, cell cycle, oxidative phosphorylation, and the unfolded protein response. Ivacaftor increased plasma concentrations of CXCL2, a neutrophil chemokine secreted by monocytes and macrophages, and CCL2, a monocyte chemokine. These results demonstrate that ivacaftor causes acute changes in blood monocytes and plasma chemokines, and suggest that increased monocyte inflammatory signals and potentially improved trafficking to the lung contribute to changes in airway inflammation in people taking CFTR modulators. To our knowledge, this is the first report investigating the transcriptomic response of isolated blood monocytes in CF subjects.

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QPCT-PDIA4 rescues ΔF508 and N1303K CFTR function in cystic fibrosis

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