Circadian control of the secretory pathway maintains collagen homeostasis

Nat Cell Biol. 2020 Jan;22(1):74-86. doi: 10.1038/s41556-019-0441-z. Epub 2020 Jan 6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator / drug effects
  • Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
  • Carbazoles / pharmacology
  • Circadian Clocks / physiology*
  • Collagen / drug effects
  • Collagen / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / drug effects
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
  • Extracellular Matrix / metabolism
  • Homeostasis / physiology*
  • Mice, Transgenic
  • Pyrrolidines / pharmacology
  • SEC Translocation Channels / drug effects
  • SEC Translocation Channels / metabolism
  • Secretory Pathway / genetics
  • Secretory Pathway / physiology*
  • Sulfonamides / pharmacology
  • Thiophenes / pharmacology
  • Vesicular Transport Proteins / drug effects
  • Vesicular Transport Proteins / metabolism


  • Carbazoles
  • KL001
  • Pyrrolidines
  • SEC Translocation Channels
  • SR9009
  • Sulfonamides
  • TANGO protein, mouse
  • Thiophenes
  • VPS33B protein, mouse
  • Vesicular Transport Proteins
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • Collagen
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4D protein, mouse