Rudd Justin C, Smits Jos P H, Kuwong Patrick T, Johnson Rachel E, Monga Louise M N, van Vlijmen-Willems Ivonne M J J, Porter Greer L, Halloran Peter O, Sharma Kanika, Schmidt Karina N, Kumar Vikas, Madson Justin G, Sarkar Mrinal K, van den Bogaard Ellen H, Grunkemeyer James A, Gudjonsson Johann E, Wong Sunny Y, Simpson Cory L, Hansen Laura A
Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska, USA.
Department of Dermatology, Radboud Research Institute for Medical Innovation, Nijmegen, The Netherlands.
Nat Commun. 2025 Jul 26;16(1):6892. doi: 10.1038/s41467-025-62105-1.
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 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 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 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 dependency to distinct stages of the transport process depending on the cell of origin.
包括哺乳动物表皮最后一层存活层中的角质形成细胞在内的特化分泌细胞，利用溶酶体相关细胞器（LRO）来胞吐对组织功能至关重要的不同货物。在这里，我们证明了Flower异构体hFWE4，一种假定的钙通道，它允许突触前囊泡和溶细胞颗粒的内吞回收，也存在于表皮板层小体（LB）上，LB是一种LRO，它挤出富含蛋白质的脂质基质以最终形成表皮屏障。在分化的角质形成细胞培养物中，我们表明hFWE4阳性的类LB囊泡与一组独特的LRO运输介质相关联，并证明hFWE4从细胞内储存中释放钙，以使这些囊泡中所含货物能够在表面呈现。最后，为了支持hFWE4依赖性运输在建立表皮屏障中的关键作用，我们证明了在由角质形成细胞钙处理受损驱动的角化遗传性疾病中，这一过程失调。我们的结果为表皮LB的生物发生和运输提供了新的见解，更广泛地表明hFWE4可能作为LRO运输机制的核心组成部分，根据起源细胞的不同，赋予运输过程不同阶段钙依赖性。
