Flower Delivery: The Emergence of FLOWER (FWE) as a Multifunctional Regulator of Endo-Lysosome-Related Organelle...

In humans, the FLOWER (FWE or CACFD1) gene encodes a set of small, alternatively spliced transmembrane protein isoforms (hFWE1-4). The canonical human isoform, hFWE4, and its various orthologues, which we collectively refer to as FWE for simplicity, assumes a four transmembrane pass structure with cytosolic N- and C-termini. This topology exposes YXXΦ motifs enabling interaction with trafficking machinery and positions highly-conserved cationic residues for interaction with membrane phospholipids. While identified initially as a mediator of synaptic vesicle endocytosis in presynaptic neurons, FWE is now recognized as a critical mediator of endo-lysosome related organelle (ELRO) trafficking across diverse cell types including cytotoxic T-lymphocytes and epidermal keratinocytes. A unifying feature of FWE function appears to be elevation of cytosolic Ca²⁺ levels. However, the underlying molecular mechanisms remain elusive. This review synthesizes current literature on FWE-mediated membrane trafficking, highlighting the evolutionary conservation of its coding sequence and tertiary structure. We propose new structure-compatible hypotheses for FWE-dependent cytosolic Ca²⁺ elevation and subsequent ELRO trafficking, highlighting experimental strategies that may aid testing of these hypotheses. Finally, we examine the distinct localizations and potential functions of non-canonical FWE isoforms.