Extracellular vesicle-mediated nuclear transport mediates key activities of the stress-regulated CLCA2 protein
Background
Inflammatory skin diseases like atopic dermatitis and psoriasis are widespread chronic inflammatory conditions affecting millions of people worldwide. They profoundly impact their quality of life. Our previous research identified chloride channel accessory 2 (CLCA2) as a protective protein in the skin's epidermis, particularly in a dry environment. Low humidity triggers hyperosmotic stress, resulting in increased levels of CLCA2, which are crucial for keratinocyte survival.
Methods an Results
We found that CLCA2 is secreted from keratinocytes via extracellular vesicles (EVs). These CLCA2-containing EVs are taken up by keratinocytes and other cell types, and CLCA2 was found at the plasma membrane and in the nucleus of the recipient cells. This discovery reveals an unexpected EV-mediated nuclear transport mechanism of transmembrane proteins. Within the nucleus, CLCA2 interacts with β-catenin, RNA binding protein 3 (RBM3), and other gene expression regulators as shown by mass-spectrometry-based interaction screening. This interaction is functionally relevant, as only CLCA2 with a nuclear localization sequence promoted Wnt target gene expression in keratinocytes, enhanced survival of these cells under hyperosmotic stress, and suppressed their migration. The co-expression of CLCA2 and RBM3 in the human epidermis points to key functions of CLCA2 and its interactors in regulating gene expression in the epidermis. Together, these results identify an unexpected nuclear function of CLCA2 in keratinocytes under homeostatic and stress conditions and suggest a role of EVs and their nuclear transport in the control of these activities.
Conclusion
Future research will reveal the role of EVs in nuclear trafficking, the interaction of CLCA2 and RBM3 in other skin diseases, and the function of these proteins in different stress conditions.
Keywords
Osmotic stress, extracellular vesicles, nuclear transport, keratinocytes, gene expression
Funding/Acknowledgments
This work was supported by grants from the Swiss National Science Foundation (310030-212212 to S.W), the ETH Zurich (Open ETH Project SKINTEGRITY.CH to S.W. and J.-C.L.) and ETH and Leopoldina postdoctoral fellowships (to K.S.). J.-C. Leroux and S.W. are members of the SKINTEGRITY.CH collaborative research program.
Authors
Kristin Seltmann1*, Britta Hettich2, Seraina Abele1, Selina Gurri1, Valeria Mantella2, Jean-Christophe Leroux2 and Sabine Werner1*(*Corresponding Author: kristin.seltmann@biol.ethz.ch)