Flower Delivery: The Emergence of FLOWER (FWE) as a Multifunctional Regulator of Endo‐Lysosome‐Related Organelle Trafficking Across Cell Types

ABSTRACT

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 Ca ²⁺ 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 Ca ²⁺ 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.