Abstract
Dysregulation of collagen synthesis is associated with disease progression in cancer and fibrosis. Collagen synthesis is coordinated with the circadian clock, which in cancer cells is, curiously, deregulated by endoplasmic reticulum (ER) stress. We hypothesized interplay between circadian rhythm, collagen synthesis, and ER stress in normal cells. Here we show that fibroblasts with ER stress lack circadian rhythms in gene expression upon clock-synchronizing time cues. Overexpression of binding immunoglobulin protein (BiP) or treatment with chemical chaperones strengthens the oscillation amplitude of circadian rhythms. The significance of these findings was explored in tendon, where we showed that BiP expression is ramped preemptively prior to a surge in collagen synthesis at night, thereby preventing protein misfolding and ER stress. In turn, this forestalls activation of the unfolded protein response in order for circadian rhythms to be maintained. Thus, targeting ER stress could be used to modulate circadian rhythm and restore collagen homeostasis in disease.—Pickard, A., Chang, J., Alachkar, N., Calverley, B., Garva, R., Arvan, P., Meng, Q.-J., Kadler, K. E. Preservation of circadian rhythms by the protein folding chaperone, BiP.
Highlights
Circadian clocks are cell-autonomous timekeeping mechanisms that occur in most tissues to optimize cellular activities in anticipation of varying demands on the cell during 24 h [1, 2]
We showed that levels of binding immunoglobulin protein (BiP) are rhythmic with a 24-h period (Metacycle Benjamini– Hochberg q-value 0.003) and its peak of expression precedes the peak of expression of pro–collagen-I protein (Fig. 1A)
Examination of chromatin immunoprecipitation sequencing data sets [23] showed that the Hspa5/BiP promoter is differentially bound by the core clock component cryptochrome protein 2 (Cry2) during the course of 24 h, with RNA polymerase II being recruited at times corresponding to elevated BiP transcription (Supplemental Fig. S1) This result was the first indication that the circadian clock had a role in preemptively averting endoplasmic reticulum (ER) stress by up-regulating BiP in anticipation of a surge in collagen synthesis
Summary
Circadian clocks are cell-autonomous timekeeping mechanisms that occur in most tissues to optimize cellular activities in anticipation of varying demands on the cell during 24 h [1, 2] One such function is control of ABBREVIATIONS: 4PBA, 4-phenylbutyric acid; ATF, activating transcription factor; BiP, binding immunoglobulin protein; COL1A1, collagen-I a1 chain; COL1A2, collagen-I a2 chain; CHOP, CCAAT-enhancer binding protein–homologous protein; collagen-I, type I collagen; ClockD19, circadian locomotor output cycles Kaput D19; ER, endoplasmic reticulum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; Grp, glucoseregulated protein; Hsp, heat shock protein; IRE1, inositol-requiring enzyme 1; iTTF, immortalized tail tendon fibroblast; MEF, mouse embryonic fibroblast; PDI, protein disulfide isomerase; Per2::luc, period circadian regulator 2–luciferase; UDCA, ursodeoxycholic acid; UPR, unfolded protein response; XBP1, X-box binding protein 1. In the experiments described below, we explored the connection between ER stress and circadian rhythm in fibroblasts actively secreting collagen
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