TY - JOUR
T1 - Circadian control of the secretory pathway maintains collagen homeostasis
AU - Chang, Joan
AU - Garva, Richa
AU - Pickard, Adam
AU - Yeung, Ching-Yan Chloé
AU - Mallikarjun, Venkatesh
AU - Swift, Joe
AU - Holmes, David F.
AU - Calverley, Ben
AU - Lu, Yinhui
AU - Adamson, Antony
AU - Raymond-Hayling, Helena
AU - Jensen, Oliver
AU - Shearer, Tom
AU - Meng, Qing Jun
AU - Kadler, Karl E.
N1 - Funding Information:
The research was funded by Wellcome (grant nos. 110126/Z/15/Z and 203128/Z/16/Z to K.E.K.), the MRC (grant no. MR/P010709/1 to Q.J.M.) and Arthritis Research UK (grant no. 20875 to Q.J.M.). V.M. was supported by a studentship from the Sir Richard Stapley Educational Trust. J.S. was funded by a Biotechnology and Biological Sciences Research Council (BBSRC) David Phillips Fellowship (grant no. BB/L024551/1). B.C. is supported by a Wellcome four-year PhD studentship (grant no. 210062/Z/17/Z). H.R.-H. is supported by a University of Manchester four-year PhD studentship. The authors would like to thank R. Schweitzer (Shriners Hospital for Children) for the Scx–Cre mice; A. Hallworth, R. Hodgkiss and M. Jackson and the University of Manchester Biological Support Facility for assistance with animal welfare and husbandry; and M. Dudek and N. Yang (University of Manchester) for assistance with bioluminescence imaging. The proteomics was performed at the Biological Mass Spectrometry Facility in the Faculty of Biology, Medicine and Health (University of Manchester) with the assistance of S. Warwood and R. O’Cualain, and electron microscopy was performed in the Electron Microscopy Facility, Faculty of Biology, Medicine and Health (University of Manchester).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/1/6
Y1 - 2020/1/6
N2 - 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.
AB - 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.
KW - Animals
KW - Aryl Hydrocarbon Receptor Nuclear Translocator/drug effects
KW - Carbazoles/pharmacology
KW - Circadian Clocks/physiology
KW - Collagen/drug effects
KW - Cyclic Nucleotide Phosphodiesterases, Type 4/drug effects
KW - Extracellular Matrix/metabolism
KW - Homeostasis/physiology
KW - Mice, Transgenic
KW - Pyrrolidines/pharmacology
KW - SEC Translocation Channels/drug effects
KW - Secretory Pathway/genetics
KW - Sulfonamides/pharmacology
KW - Thiophenes/pharmacology
KW - Vesicular Transport Proteins/drug effects
U2 - 10.1038/s41556-019-0441-z
DO - 10.1038/s41556-019-0441-z
M3 - Article
C2 - 31907414
SN - 1465-7392
VL - 22
SP - 74
EP - 86
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 1
ER -