Rediscovering the intricacies of secretory granule biogenesis.

Regulated secretion, an essential cellular process, relies on secretory granules (SGs) for the controlled release of a diverse range of cargo molecules, including proteins, peptides, hormones, enzymes, and neurotransmitters. SG biogenesis encompasses cargo selection, sorting, packaging, and trafficking, with the trans-Golgi Network (TGN) playing a central role. Research in the last three decades has revealed significant components required for SG biogenesis; however, no cargo receptor transferring granule cargo from the TGN to immature SGs (ISGs) has yet been identified. Consequently, recent research has devoted significant attention to studying receptor-independent cargo sorting mechanisms, shedding new light on the complexities of regulated secretion. Understanding the underlying molecular and biophysical mechanisms behind cargo sorting into ISGs holds great promise for advancing our knowledge of cellular communication and disease mechanisms.