Circadian Clock Regulation of the Secretory Pathway

Proteins destined for secretion move from the endoplasmic reticulum (ER, the site of synthesis) to Golgi cisternae then onto the cell surface in transport vesicles. Although the mechanism of anterograde and retrograde transport via vesicles is well understood the temporal coordination of transport between organelles has not been studied. Here we show that the extracellular levels of collagen-I (the most abundant protein in vertebrates) are 24-h rhythmic in tendon, which is the richest source of collagen-I. Rhythmicity is the result of circadian clock control of the secretory pathway via ER-ribosome docking, Tango1-dependent ER export, phosphodiesterase-dependent Golgi-ER retrograde transport of Hsp47 (a collagen molecular chaperone), and Vps33b-dependent post Golgi export, which pause collagen-I transport at each node in the pathway during a 24-hour cycle. The structure and mechanical properties of tendon are also 24-hourly rhythmic. Thus, the circadian clock is a master logistic operator of the secretory pathway in mammalian cells.