Circadian control of the secretory pathway maintains collagen homeostasis

Joan Chang; Richa Garva; Adam Pickard; Ching Yan Chloé Yeung; Venkatesh Mallikarjun; Joe Swift; David Holmes; Ben Calverley; Yinhui Lu; Antony Adamson; Helena Raymond-Hayling; Oliver Jensen; Tom Shearer; Qing-Jun Meng; Karl Kadler

doi:10.1038/s41556-019-0441-z

Circadian control of the secretory pathway maintains collagen homeostasis

Joan Chang, Richa Garva, Adam Pickard, Ching Yan Chloé Yeung, Venkatesh Mallikarjun, Joe Swift, David Holmes, Ben Calverley, Yinhui Lu, Antony Adamson, Helena Raymond-Hayling, Oliver Jensen, Tom Shearer, Qing-Jun Meng, Karl Kadler

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Abstract

Collagen is the most abundant secreted protein in vertebrates and persists throughout life without renewal. The permanency of collagen networks contrasts with continued collagen synthesis throughout adulthood and with conventional transcriptional/translational homeostatic mechanisms that replace damaged proteins with new copies. Here we show circadian clock regulation of ER-to-plasma membrane procollagen transport 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 and degradation affects a pool of newly synthesised collagen whilst maintaining the persistent collagen network. Disabling the circadian clock causes abnormal collagen fibrils and collagen accumulation which is reduced in vitro by 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.

Original language	English
Pages (from-to)	74-86
Number of pages	13
Journal	Nature Cell Biology
Volume	22
Issue number	1
DOIs	https://doi.org/10.1038/s41556-019-0441-z
Publication status	Published - 6 Jan 2020

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title = "Circadian control of the secretory pathway maintains collagen homeostasis",

abstract = "Collagen is the most abundant secreted protein in vertebrates and persists throughout life without renewal. The permanency of collagen networks contrasts with continued collagen synthesis throughout adulthood and with conventional transcriptional/translational homeostatic mechanisms that replace damaged proteins with new copies. Here we show circadian clock regulation of ER-to-plasma membrane procollagen transport 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 and degradation affects a pool of newly synthesised collagen whilst maintaining the persistent collagen network. Disabling the circadian clock causes abnormal collagen fibrils and collagen accumulation which is reduced in vitro by 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.",

author = "Joan Chang and Richa Garva and Adam Pickard and Yeung, {Ching Yan Chlo{\'e}} and Venkatesh Mallikarjun and Joe Swift and David Holmes and Ben Calverley and Yinhui Lu and Antony Adamson and Helena Raymond-Hayling and Oliver Jensen and Tom Shearer and Qing-Jun Meng and Karl Kadler",

note = "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{\textquoteright}Cualain, and electron microscopy was performed in the Electron Microscopy Facility, Faculty of Biology, Medicine and Health (University of Manchester). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

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doi = "10.1038/s41556-019-0441-z",

language = "English",

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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

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

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 continued collagen synthesis throughout adulthood and with conventional transcriptional/translational homeostatic mechanisms that replace damaged proteins with new copies. Here we show circadian clock regulation of ER-to-plasma membrane procollagen transport 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 and degradation affects a pool of newly synthesised collagen whilst maintaining the persistent collagen network. Disabling the circadian clock causes abnormal collagen fibrils and collagen accumulation which is reduced in vitro by 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 continued collagen synthesis throughout adulthood and with conventional transcriptional/translational homeostatic mechanisms that replace damaged proteins with new copies. Here we show circadian clock regulation of ER-to-plasma membrane procollagen transport 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 and degradation affects a pool of newly synthesised collagen whilst maintaining the persistent collagen network. Disabling the circadian clock causes abnormal collagen fibrils and collagen accumulation which is reduced in vitro by 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.

U2 - 10.1038/s41556-019-0441-z

DO - 10.1038/s41556-019-0441-z

M3 - Article

SN - 1465-7392

VL - 22

SP - 74

EP - 86

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 1

ER -

Circadian control of the secretory pathway maintains collagen homeostasis

Abstract

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