Open Access

Inhibitors of the ubiquitin‑proteasome system rescue cellular levels and ion transport function of pathogenic pendrin (SLC26A4) protein variants

  • Authors:
    • Emanuele Bernardinelli
    • Rapolas Jamontas
    • Arnoldas Matulevičius
    • Florian Huber
    • Houssein Nasser
    • Sophie Klaus
    • Haixia Zhu
    • Jiangang Gao
    • Silvia Dossena
  • View Affiliations

  • Published online on: February 28, 2025     https://doi.org/10.3892/ijmm.2025.5510
  • Article Number: 69
  • Copyright: © Bernardinelli et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pendrin (SLC26A4) is an anion exchanger abundantly expressed in the inner ear, kidney and thyroid, and its malfunction resulting from genetic mutation leads to Pendred syndrome and non‑syndromic deafness DFNB4. Pathogenic variants of the pendrin protein are less expressed than the wild‑type, but the mechanism underlying this phenomenon is unknown. In the present study, the hypothesis that reduced protein expression stems from increased protein degradation was explored. To verify this hypothesis, the protein levels and anion transport function of several pathogenic pendrin variants were measured following exposure to inhibitors of the ubiquitin‑proteasome system (UPS) and the lysosomal/autophagosomal pathways. Protein levels were measured by western blotting and quantitative imaging; ion transport was measured with a fluorometric method. Post‑translational modification of pendrin was investigated by immunoprecipitation and mass spectrometry. The results showed that the protein abundance and half‑life of pathogenic pendrin variants were significantly reduced compared with the wild‑type in cell‑based assays and in a mouse model of Pendred syndrome/DFNB4, pointing to accelerated protein degradation rather than defective protein production. Wild‑type pendrin and its variants are abundantly but differentially ubiquitinated, consistent with their different protein stability. While ubiquitination at the C‑terminus controls the stability of wild‑type pendrin, preferential ubiquitination of lysine 77 occurred in the pathogenic pendrin variant p.R409H. Inhibition of the UPS with investigational (MG132) or clinical (bortezomib, delanzomib, or carfilzomib) proteasome inhibitors rescued the expression, plasma membrane targeting, and ion transport function of pathogenic pendrin variants, while inhibition of the lysosomal/autophagosomal pathway was ineffective. Among the compounds tested, carfilzomib rescued the ion transport of pendrin p.R409H to wild‑type levels. These findings suggest that targeting specific molecular players within the UPS can rescue the expression and activity of pathogenic variants of the pendrin protein, which represents a novel therapeutic concept for Pendred syndrome/DFNB4. 
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May-2025
Volume 55 Issue 5

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Bernardinelli E, Jamontas R, Matulevičius A, Huber F, Nasser H, Klaus S, Zhu H, Gao J and Dossena S: Inhibitors of the ubiquitin‑proteasome system rescue cellular levels and ion transport function of pathogenic pendrin (SLC26A4) protein variants. Int J Mol Med 55: 69, 2025.
APA
Bernardinelli, E., Jamontas, R., Matulevičius, A., Huber, F., Nasser, H., Klaus, S. ... Dossena, S. (2025). Inhibitors of the ubiquitin‑proteasome system rescue cellular levels and ion transport function of pathogenic pendrin (SLC26A4) protein variants. International Journal of Molecular Medicine, 55, 69. https://doi.org/10.3892/ijmm.2025.5510
MLA
Bernardinelli, E., Jamontas, R., Matulevičius, A., Huber, F., Nasser, H., Klaus, S., Zhu, H., Gao, J., Dossena, S."Inhibitors of the ubiquitin‑proteasome system rescue cellular levels and ion transport function of pathogenic pendrin (SLC26A4) protein variants". International Journal of Molecular Medicine 55.5 (2025): 69.
Chicago
Bernardinelli, E., Jamontas, R., Matulevičius, A., Huber, F., Nasser, H., Klaus, S., Zhu, H., Gao, J., Dossena, S."Inhibitors of the ubiquitin‑proteasome system rescue cellular levels and ion transport function of pathogenic pendrin (SLC26A4) protein variants". International Journal of Molecular Medicine 55, no. 5 (2025): 69. https://doi.org/10.3892/ijmm.2025.5510