ArticleCellular & molecular biology letters2026
PDIA6 promotes the cell proliferation of ESCC by enhancing the disulfide bond formation in TRAF4.
Article in Cellular & molecular biology letters, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Quantitative interactome mapping of skeletal muscle insulin resistance.Molecular systems biology · 2026Article
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17 authors.
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Abstract
backgroundProtein disulfide isomerase A6 (PDIA6), a member of the PDI family, catalyzes disulfide bond formation and assists protein folding. However, its function in esophageal squamous cell carcinoma (ESCC) remains largely unknown.
methodsFunctional experiments, including CRISPR/Cas9 knockout, overexpression, rescue assays, and patient-derived xenograft (PDX) models, were performed to evaluate the role of PDIA6 in ESCC proliferation and tumor growth. Pull down-mass spectrometry assays, co-immunoprecipitation, and protein-protein docking assays were used to investigate PDIA6–tumor necrosis factor receptor-associated factor 4 (TRAF4) interactions and disulfide bond formation. Ubiquitination and cycloheximide chase assays were applied to assess the stability of TRAF4. Antisense oligonucleotides (ASOs) targeting PDIA6 were tested for therapeutic efficacy in vitro and in vivo.
resultsWe found PDIA6 was markedly upregulated in ESCC tissues, with a positive correlation to a poor prognosis. Functional assays demonstrated that PDIA6 significantly promoted the proliferation of ESCC cells both in vitro and in vivo. A pull down–mass spectrometry assay identified TRAF4 as a direct binding partner of PDIA6. Protein-protein docking revealed that PDIA6 interacted with the N-terminal (1-277) domain of TRAF4, enhancing disulfide bond formation at Cys39/Cys42 and Cys83/Cys106. These bonds were indispensable for TRAF4’s E3 ubiquitin ligase activity in facilitating the ubiquitination of AKT. PDIA6 further stabilized TRAF4 by competing with SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1), thereby preventing TRAF4 ubiquitination and proteasomal degradation. The absence of PDIA6 led to the destabilization of TRAF4, resulting in the inactivation of the AKT/mTOR pathway. Rescue experiments using TRAF4 C42A or C83A mutants failed to restore AKT signaling or tumor growth. Notably, ASOs targeting PDIA6 suppressed ESCC growth in vitro and in patient-derived xenografts.
conclusionsPDIA6 drives ESCC progression by stabilizing TRAF4 and sustaining AKT/mTOR signaling. Targeting PDIA6 with ASOs offers a promising therapeutic strategy for ESCC.
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