Endoplasmic reticulum Ca2+ depletion activates XBP1 and controls terminal differentiation in keratinocytes and epidermis

Authors


  • Funding sources
    This work was supported by National Institutes of Health grants AR051930 (T.M.) and AR19098 (P.E.) and the San Francisco Veterans’ Affairs Medical Center.

  • Conflicts of interest
    None declared.

Anna Celli.
E-mail: celli.anna@gmail.com

Summary

Background  Endoplasmic reticulum (ER) Ca2+ depletion, previously shown to signal pathological stress responses, has more recently been found also to trigger homeostatic physiological processes such as differentiation. In keratinocytes and epidermis, terminal differentiation and barrier repair require physiological apoptosis and differentiation, as evidenced by protein synthesis, caspase 14 expression, lipid secretion and stratum corneum (SC) formation.

Objectives  To investigate the role of Ca2+ depletion-induced ER stress in keratinocyte differentiation and barrier repair in vivo and in cell culture.

Methods  The SERCA2 Ca2+ pump inhibitor thapsigargin (TG) was used to deplete ER calcium both in cultured keratinocytes and in mice. Levels of the ER stress factor XBP1, loricrin, caspase 14, lipid synthesis and intracellular Ca2+ were compared after both TG treatment and barrier abrogation.

Results  We showed that these components of terminal differentiation and barrier repair were signalled by physiological ER stress, via release of stratum granulosum (SG) ER Ca2+ stores. We first found that keratinocyte and epidermal ER Ca2+ depletion activated the ER-stress-induced transcription factor XBP1. Next, we demonstrated that external barrier perturbation resulted in both intracellular Ca2+ emptying and XBP1 activation. Finally, we showed that TG treatment of intact skin did not perturb the permeability barrier, yet stimulated and mimicked the physiological processes of barrier recovery.

Conclusions  This report is the first to quantify and localize ER Ca2+ loss after barrier perturbation and show that homeostatic processes that restore barrier function in vivo can be reproduced solely by releasing ER Ca2+, via induction of physiological ER stress.

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