Protection of circadian rhythms by the protein folding chaperone, BiP

Abstract

ER stress and dysregulation of collagen synthesis are associated with progression of disease in cancer and fibrosis. Collagen synthesis is co-ordinated by the circadian clock, and in cancer cells, ER stress induces a phase shift in circadian oscillations. We hypothesised that an interplay exists between circadian rhythm, collagen synthesis and ER stress in normal cells. Here we show that fibroblasts with ER stress cannot respond to circadian cues. Conversely, overexpression of BiP or treatment with chemical chaperones strengthen circadian rhythms. The significance of these findings was explored in tendon. We showed that BiP expression is ramped pre-emptively prior to a surge in collagen synthesis at night, thereby preventing protein misfolding and ER stress. In turn, we propose, 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.