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Collagen is the most abundant secreted protein in vertebrates and persists throughout life without renewal. The permanency of collagen networks contrasts with both the continued synthesis of collagen throughout adulthood and the conventional transcriptional/translational homeostatic mechanisms that replace damaged proteins with new copies. Here, we show circadian clock regulation of endoplasmic reticulum-to-plasma membrane procollagen transport by the sequential rhythmic expression of SEC61, TANGO1, PDE4D and VPS33B. The result is nocturnal procollagen synthesis and daytime collagen fibril assembly in mice. Rhythmic collagen degradation by CTSK maintains collagen homeostasis. This circadian cycle of collagen synthesis and degradation affects a pool of newly synthesized collagen, while maintaining the persistent collagen network. Disabling the circadian clock causes abnormal collagen fibrils and collagen accumulation, which are reduced in vitro by the NR1D1 and CRY1/2 agonists SR9009 and KL001, respectively. In conclusion, our study has identified a circadian clock mechanism of protein homeostasis wherein a sacrificial pool of collagen maintains tissue function.


Joan Chang, Richa Garva, Adam Pickard, Ching-Yan ChloƩ Yeung, Venkatesh Mallikarjun, Joe Swift, David F Holmes, Ben Calverley, Yinhui Lu, Antony Adamson, Helena Raymond-Hayling, Oliver Jensen, Tom Shearer, Qing Jun Meng, Karl E Kadler. Circadian control of the secretory pathway maintains collagen homeostasis. Nature cell biology. 2020 Jan;22(1):74-86

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PMID: 31907414

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