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CLIP2 : a novel functional player in AQP5 trafficking dynamics and implications for Sjögren’s disease

D’Agostino, Claudia ; Filipovic, Nikola ; Zindy, Egor ; Conrard, Louise ; Wang, Zhen ; Moscato, Stefania ; Engelke, Fiona ; Nash, Angelica LU ; Hagströmer, Carl Johan LU orcid and Strandberg, Helin LU , et al. (2025) In Cell Communication and Signaling 23(1).
Abstract

Background: Sjögren’s disease (SjD) is an autoimmune condition affecting exocrine glands, resulting in decreased saliva and tear production. Aquaporin 5 (AQP5) is a transmembrane water channel playing a central role in water transport. In SjD, deregulation of AQP5 expression, trafficking and interactions with various proteins contribute to the underlying disease mechanisms. Methods: Co-immunoprecipitation followed by mass spectrometry, proximity ligation assay, microscale thermophoresis and in-silico modelling were carried out to investigate protein-protein interaction. CRISPR/Cas9-mediated knockout was performed in a salivary gland cell line stably transfected with AQP5. Protein colocalization and AQP5 trafficking were studied by... (More)

Background: Sjögren’s disease (SjD) is an autoimmune condition affecting exocrine glands, resulting in decreased saliva and tear production. Aquaporin 5 (AQP5) is a transmembrane water channel playing a central role in water transport. In SjD, deregulation of AQP5 expression, trafficking and interactions with various proteins contribute to the underlying disease mechanisms. Methods: Co-immunoprecipitation followed by mass spectrometry, proximity ligation assay, microscale thermophoresis and in-silico modelling were carried out to investigate protein-protein interaction. CRISPR/Cas9-mediated knockout was performed in a salivary gland cell line stably transfected with AQP5. Protein colocalization and AQP5 trafficking were studied by immunofluorescence. Autoantibodies were quantified by ELISA. Results: We identified CAP-Gly Domain Containing Linker Protein 2 (CLIP2) as a novel AQP5-interacting partner. Structural modeling of the AQP5-CLIP2 interaction revealed that the interaction is similar to other CAP-Gly domain complexes. Functional investigations indicated CLIP2 significantly influences AQP5 trafficking to the plasma membrane. Furthermore, interactions of CLIP2 with other AQP5 partners reveal the possible formation of multiprotein complexes in salivary glands. In SjD patients, alterations in these complexes and the presence of autoantibodies against AQP5, CLIP2, and other AQP5-interacting partners such as Ezrin and prolactin-inducible protein (PIP) may also contribute to disease pathogenesis. Conclusion: Our study identifies CLIP2 as a novel player in the AQP5 interactome and sheds light on its crucial role in AQP5 trafficking. In SjD, the alterations in AQP5-CLIP2 interactions and the presence of autoantibodies against both proteins highlighted their potential as targets for future therapeutic interventions in SjD.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aquaporin 5, Autoantibodies, CAP-Gly Domain Containing LinkerProtein, Protein-protein interaction, Salivary gland, Sjöögren's disease
in
Cell Communication and Signaling
volume
23
issue
1
article number
473
publisher
BioMed Central (BMC)
external identifiers
  • pmid:41184862
  • scopus:105020703530
ISSN
1478-811X
DOI
10.1186/s12964-025-02476-6
language
English
LU publication?
yes
id
294fbe82-16cc-442e-b010-dd44e93df84b
date added to LUP
2025-12-09 14:43:27
date last changed
2025-12-09 14:43:59
@article{294fbe82-16cc-442e-b010-dd44e93df84b,
  abstract     = {{<p>Background: Sjögren’s disease (SjD) is an autoimmune condition affecting exocrine glands, resulting in decreased saliva and tear production. Aquaporin 5 (AQP5) is a transmembrane water channel playing a central role in water transport. In SjD, deregulation of AQP5 expression, trafficking and interactions with various proteins contribute to the underlying disease mechanisms. Methods: Co-immunoprecipitation followed by mass spectrometry, proximity ligation assay, microscale thermophoresis and in-silico modelling were carried out to investigate protein-protein interaction. CRISPR/Cas9-mediated knockout was performed in a salivary gland cell line stably transfected with AQP5. Protein colocalization and AQP5 trafficking were studied by immunofluorescence. Autoantibodies were quantified by ELISA. Results: We identified CAP-Gly Domain Containing Linker Protein 2 (CLIP2) as a novel AQP5-interacting partner. Structural modeling of the AQP5-CLIP2 interaction revealed that the interaction is similar to other CAP-Gly domain complexes. Functional investigations indicated CLIP2 significantly influences AQP5 trafficking to the plasma membrane. Furthermore, interactions of CLIP2 with other AQP5 partners reveal the possible formation of multiprotein complexes in salivary glands. In SjD patients, alterations in these complexes and the presence of autoantibodies against AQP5, CLIP2, and other AQP5-interacting partners such as Ezrin and prolactin-inducible protein (PIP) may also contribute to disease pathogenesis. Conclusion: Our study identifies CLIP2 as a novel player in the AQP5 interactome and sheds light on its crucial role in AQP5 trafficking. In SjD, the alterations in AQP5-CLIP2 interactions and the presence of autoantibodies against both proteins highlighted their potential as targets for future therapeutic interventions in SjD.</p>}},
  author       = {{D’Agostino, Claudia and Filipovic, Nikola and Zindy, Egor and Conrard, Louise and Wang, Zhen and Moscato, Stefania and Engelke, Fiona and Nash, Angelica and Hagströmer, Carl Johan and Strandberg, Helin and Parisis, Dorian and Datlibagi, Azine and Gregoire, Françoise and Bolaky, Nargis and Tarabichi, Maxime and Soyfoo, Muhammad Shahnawaz and Schey, Kevin L. and Dörner, Thomas and Witte, Torsten and Perret, Jason and Mattii, Letizia and Törnroth-Horsefield, Susanna and Delporte, Christine}},
  issn         = {{1478-811X}},
  keywords     = {{Aquaporin 5; Autoantibodies; CAP-Gly Domain Containing LinkerProtein; Protein-protein interaction; Salivary gland; Sjöögren's disease}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Cell Communication and Signaling}},
  title        = {{CLIP2 : a novel functional player in AQP5 trafficking dynamics and implications for Sjögren’s disease}},
  url          = {{http://dx.doi.org/10.1186/s12964-025-02476-6}},
  doi          = {{10.1186/s12964-025-02476-6}},
  volume       = {{23}},
  year         = {{2025}},
}