The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

• Published in: Traffic (Copenhagen, Denmark) Denmark), 2019-06, Vol.20 (6), p.404-435
• Main Authors: Bowman, Shanna L., Bi‐Karchin, Jing, Le, Linh, Marks, Michael S.
• Format: Article
• Language: English
• Subjects: alpha granule; AP‐3; BLOC‐1; BLOC‐2; BLOC‐3; Chediak‐Higashi syndrome; Cytotoxicity; dense granule; Epithelial cells; Granule cells; Griscelli syndrome; Hemostasis; Hermansky‐Pudlak syndrome; HOPS; Keratinocytes; lamellar body; Lymphocytes T; melanosome; Melanosomes; Natural killer cells; Organelles; RAB27A; RAB32; RAB38; Rare diseases; Skin; VPS33A; VPS33B; Weibel‐Palade body
• ISSN: 1398-9219; 1600-0854
• DOI: 10.1111/tra.12646

Lysosome‐related organelles (LROs) comprise a diverse group of cell type‐specific, membrane‐bound subcellular organelles that derive at least in part from the endolysosomal system but that have unique contents, morphologies and functions to support specific physiological roles. They include: melanosomes that provide pigment to our eyes and skin; alpha and dense granules in platelets, and lytic granules in cytotoxic T cells and natural killer cells, which release effectors to regulate hemostasis and immunity; and distinct classes of lamellar bodies in lung epithelial cells and keratinocytes that support lung plasticity and skin lubrication. The formation, maturation and/or secretion of subsets of LROs are dysfunctional or entirely absent in a number of hereditary syndromic disorders, including in particular the Hermansky‐Pudlak syndromes. This review provides a comprehensive overview of LROs in humans and model organisms and presents our current understanding of how the products of genes that are defective in heritable diseases impact their formation, motility and ultimate secretion. Lysosome‐related organelles (LROs) are cell type‐specific subcellular structures that derive from both the secretory and endolysosomal pathways and that play key roles in numerous physiological systems, in most cases following stimulus‐dependent secretion of their contents. The biogenesis and/or secretion of LRO subsets are disrupted in hereditary syndromic disorders such as the Hermansky‐Pudlak syndromes and familial hemophagocytic lymphohistiocytosis. We comprehensively review LROs in humans and model organisms and the mechanisms by which products of disease genes regulate their formation, motility and ultimate secretion.