Circadian Clock Regulation of the Secretory Pathway

Ching-Yan Chloé Yeung, Richa Garva, Adam Pickard, Joan Chang, David F. Holmes, Yinhui Lu, Venkatesh Mallikarjun, Joe Swift, Antony Adamson, Ben Calverley, Qing Jun Meng, Karl E. Kadler

Research output: Contribution to journalArticlepeer-review


Collagen is the most abundant secreted protein in vertebrates that persists throughout life without renewal. The unchanging nature of collagen contrasts with observed continued collagen synthesis throughout adulthood and with conventional transcriptional and translational homeostatic mechanisms that replace damaged proteins with new copies. Here we show circadian clock regulation of procollagen transport from ER-to-Golgi and Golgi-to-plasma membrane by 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, assembly and degradation affects only a pool of newly-synthesized collagen whilst maintaining the persistent collagen network. Disabling the circadian clock causes collagen accumulation and abnormal fibrils in vivo. In conclusion, our study has identified a circadian clock mechanism of protein homeostasis in which a sacrificial pool of collagen is synthesized and removed to maintain tissue function.
Original languageEnglish
Pages (from-to)74-86
JournalNature Cell Biology
Publication statusPublished - 6 Jan 2020


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