Flower dependent trafficking of lamellar bodies facilitates maturation of the epidermal barrier
Specialized secretory cells, including keratinocytes in the last viable layers of mammalian epidermis, utilize lysosome-related organelles (LROs) to exocytose distinct cargoes vital for tissue function. Here, we demonstrate that the Flower isoform, hFWE4, a putative Ca<sup>2+</sup> channel that permits endocytic retrieval of presynaptic vesicles and lytic granules, also resides on epidermal lamellar bodies (LBs), an LRO that extrudes a proteinaceous lipid-rich matrix to finalize the epidermal barrier. In differentiated keratinocyte cultures, we show that hFWE4-positive LB-like vesicles associate with a distinct ensemble of LRO trafficking mediators and demonstrate that hFWE4 liberates Ca<sup>2+</sup> from intracellular stores to enable the surface presentation of cargo contained within these vesicles. Finally, supporting a critical role for hFWE4-dependent trafficking in establishing the epidermal barrier, we demonstrate that this process is dysregulated in genetic diseases of cornification that are driven by impairments in keratinocyte Ca<sup>2+</sup> handling. Our results provide new insight into the biogenesis and trafficking of epidermal LBs and more broadly suggest that hFWE4 may serve as a core component of LRO trafficking machinery that endows Ca<sup>2+</sup> dependency to distinct stages of the transport process depending on the cell of origin.
Authors
- Jos P.H. Smits (ORCID: https://orcid.org/0000-0003-0915-8624)
- Rachel Johnson (ORCID: https://orcid.org/0000-0002-9408-4924)
- Vikas Kumar (ORCID: https://orcid.org/0000-0001-7516-7807)
- Ivonne M.J.J. van Vlijmen‐Willems (ORCID: https://orcid.org/0000-0002-3522-2573)
- Cory L. Simpson (ORCID: https://orcid.org/0000-0002-3933-6404)
- Justin C. Rudd
- Mrinal K. Sarkar (ORCID: https://orcid.org/0000-0001-8505-4259)
- James A. Grunkemeyer
- Louise Monga
- Karina N. Schmidt
- George Arthur Porter Jr. (ORCID: https://orcid.org/0000-0003-0726-9988)
- Johann Eli Gudjonsson (ORCID: https://orcid.org/0000-0002-0080-0812)
- Philip F. Halloran (ORCID: https://orcid.org/0000-0003-1371-1947)
- Ellen H. van den Bogaard (ORCID: https://orcid.org/0000-0003-4846-0287)
- Justin G. Madson
- Kanika Sharma (ORCID: https://orcid.org/0000-0001-7847-4319)
- Sunny Y. Wong (ORCID: https://orcid.org/0000-0002-0222-2681)
- Laura A. Hansen (ORCID: https://orcid.org/0000-0003-3436-8412)
- Patrick T Kuwong (ORCID: https://orcid.org/0009-0004-0906-0453)
Institutions
- Creighton University (US)
- Nebraska Medical Center (US)
- Radboud University Nijmegen (NL)
- University of Massachusetts Chan Medical School (US)
- University of Washington (US)
- University of Michigan (US)
- Radboud University Medical Center (NL)
- Düsseldorf University Hospital (DE)
- Radboud Institute for Molecular Life Sciences (NL)
- Heinrich Heine University Düsseldorf (DE)
- University of Nebraska Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-26
- DOI
- https://doi.org/10.1038/s41467-025-62105-1
- Citations
- 3
- Primary Topic
- Plant Reproductive Biology
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Creighton University
- Universität des Saarlandes
- National Institutes of Health
- Penn Skin Biology and Diseases Resource-based Center, University of Pennsylvania
- National Institute of Arthritis and Musculoskeletal and Skin Diseases