Biogenesis of specialized lysosomes in differentiated keratinocytes relies on close apposition with the Golgi apparatus

Abstract Intracellular organelles support cellular physiology in diverse conditions. In the skin, epidermal keratinocytes undergo differentiation with gradual changes in cellular physiology, accompanying remodeling in lysosomes and the Golgi apparatus. However, the functional significance and the molecular link between lysosome and Golgi remodeling were unknown. Here, we show that in differentiated keratinocytes, the Golgi apparatus redistributes as ministacks leading to a significant increase in total protein secretion. The Golgi ministacks establish contact with lysosomes facilitated by Golgi tethering protein GRASP65, the depletion of which is associated with the loss of Golgi-lysosome contact and malformation of lysosomes defined by their aberrant morphology, size, and function. Strikingly, these lysosomes receive secretory Golgi cargoes, contribute to the protein secretion from the Golgi, and are critically maintained by the secretory function of the Golgi apparatus. We uncovered a novel mechanism of lysosome specialization through unique Golgi-lysosome contact that likely supports high secretion from differentiated keratinocytes. Key points Calcium induced differentiation of human keratinocytes accompanies the dispersal of functional Golgi stacks and lysosomes. Dispersed Golgi stacks establish contact/physical apposition with the lysosomes. Golgi tether GRASP65 surrounds keratinocyte lysosomes and facilitates Golgi-lysosome apposition. GRASP65 depletion abolishes Golgi-lysosome apposition and accumulates morphologically altered non-degradative lysosomes. Lysosomes of differentiated keratinocytes receive secretory Golgi cargo and contribute to the protein secretion from the Golgi. Specialized lysosomes are maintained by the secretory function of the Golgi apparatus.