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

Celli, Anna; Mackenzie, Donald; Crumrine, Debbie; Tu, Chia-Ling; Hupe, Melanie; Bikle, Daniel D.; Elias, Peter M.; Mauro, Theodora M.

doi:10.1111/j.1365-2133.2010.10046.x

Cited by 59 publications

(49 citation statements)

References 38 publications

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“…The profilaggrin AB domain contains a functional calciumbinding domain, homologous to that of the S100-family of proteins (Markova et al, 1993), and thus it is tempting to speculate that this domain has biological functions similar to other S100 proteins (Marenholz et al, 2004). Changes in the level of calcium-binding proteins may alter the calcium gradient in the epidermis by regulating the ratio of free versus bound intracellular calcium (Celli et al, 2011) and consequently triggering a signaling mechanism affecting epidermal homeostasis. Profilaggrin and another fused type S100-protein hornerin, are present at high levels in the normal epidermis, but are substantially downregulated in psoriasis (Takaishi et al, 2005;Huffmeier et al, 2007;Zhao et al, 2007), which is consistent with our observation on profilaggrin playing an inhibitory role on keratinocyte proliferation.…”

Section: Discussionmentioning

confidence: 99%

Regulatory Role for the Profilaggrin N-Terminal Domain in Epidermal Homeostasis

Aho

Harding

Lee

et al. 2012

Journal of Investigative Dermatology

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It is well known that profilaggrin, after its release from keratohyalin granules through dephosphorylation, becomes enzymatically processed into individual filaggrin monomers. The roles for filaggrin monomers in aggregating keratin filaments, as a component of the cornified cell envelope, and as a source of natural moisturizing factor are well established. A specific N-terminal fragment, called the PF-AB domain, becomes proteolytically released as well, but much less is known about its functional role in epidermal development. Here, the functional role of profilaggrin N-terminal (PF-N) domain was addressed by overexpressing three overlapping fragments from a lentiviral expression vector in the epidermis of living skin equivalents. The PF-N domain expression impaired the epidermal development through reducing keratinocyte proliferation and impairing differentiation. The expression of well-known differentiation markers profilaggrin, loricrin, and keratin 10 was considerably downregulated in PF-N domain overexpressing-skin equivalents. The activation of caspase 14 was also substantially affected. In contrast, total silencing of profilaggrin expression, obtained with a lentiviral miR vector, resulted in a hyperproliferative epidermis. We propose a hypothesis that profilaggrin AB domain provides a key feedback mechanism that controls epidermal homeostasis.

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Section: Discussionmentioning

confidence: 99%

Regulatory Role for the Profilaggrin N-Terminal Domain in Epidermal Homeostasis

Aho

Harding

Lee

et al. 2012

Journal of Investigative Dermatology

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“…At lower Ca 2+ concentrations in the basal layer, the keratinocytes proliferate, whereas at higher Ca 2+ concentrations in the suprabasal layer, terminal differentiation is triggered (Denda et al, 2000;Bikle et al, 2012). Celli et al succeeded in quantifying Ca 2+ depletion from the epidermal strata induced by acute barrier perturbation using tape-stripping (Celli et al, 2011). The damaged epidermis showed a remarkable decline in Ca 2+ concentration from 20 mM to ,1.5 mM.…”

Section: Introductionmentioning

confidence: 99%

Mechanosensitive ATP release from hemichannels and Ca2+ influx through TRPC6 accelerate wound closure in keratinocytes

Takada

Furuya

Sokabe

2014

Journal of Cell Science

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Cutaneous wound healing is accelerated by exogenous mechanical forces and is impaired in TRPC6-knockout mice. Therefore, we designed experiments to determine how mechanical force and TRPC6 channels contribute to wound healing using HaCaT keratinocytes. HaCaT cells were pretreated with hyperforin, a major component of a traditional herbal medicine for wound healing and also a TRPC6 activator, and cultured in an elastic chamber. At 3 h after scratching the confluent cell layer, the ATP release and intracellular Ca 2+ increases in response to stretching (20%) were live-imaged. ATP release was observed only in cells at the frontier facing the scar. The diffusion of released ATP caused intercellular Ca 2+ waves that propagated towards the rear cells in a P2Y-receptor-dependent manner. The Ca 2+ response and wound healing were inhibited by ATP diphosphohydrolase apyrase, the P2Y antagonist suramin, the hemichannel blocker CBX and the TRPC6 inhibitor diC8-PIP 2 . Finally, the hemichannel-permeable dye calcein was taken up only by ATP-releasing cells. These results suggest that stretch-accelerated wound closure is due to the ATP release through mechanosensitive hemichannels from the foremost cells and the subsequent Ca 2+ waves mediated by P2Y and TRPC6activation.

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“…Prior studies demonstrated that various unrelated external perturbations, including UV B (UVB) irradiation, wounding, and permeability barrier abrogation, induce endoplasmic reticulum (ER) stress (3), which in turn stimulates a set of responses that rescue cells from apoptosis (4). These responses include increased expression of CAMP in epithelial tissues such as mammalian epidermis (5)(6)(7)(8).…”

mentioning

confidence: 99%

A Novel Role of a Lipid Species, Sphingosine-1-Phosphate, in Epithelial Innate Immunity

Park

Elias

Shin

et al. 2013

Molecular and Cellular Biology

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A variety of external perturbations can induce endoplasmic reticulum (ER) stress, followed by stimulation of epithelial cells to produce an innate immune element, the cathelicidin antimicrobial peptide (CAMP). ER stress also increases production of the proapoptotic lipid ceramide and its antiapoptotic metabolite, sphingosine-1-phosphate (S1P). We demonstrate here that S1P mediates ER stress-induced CAMP generation. Cellular ceramide and S1P levels rose in parallel with CAMP levels following addition of either exogenous cell-permeating ceramide (C2Cer), which increases S1P production, or thapsigargin (an ER stressor), applied to cultured human skin keratinocytes or topically to mouse skin. Knockdown of S1P lyase, which catabolizes S1P, enhanced ER stress-induced CAMP production in cultured cells and mouse skin. These and additional inhibitor studies show that S1P is responsible for ER stress-induced upregulation of CAMP expression. Increased CAMP expression is likely mediated via S1P-dependent NF-B-C/EBP␣ activation. Finally, lysates of both ER-stressed and S1P-stimulated cells blocked growth of virulent Staphylococcus aureus in vitro, and topical C2Cer and LL-37 inhibited invasion of Staphylococcus aureus into murine skin. These studies suggest that S1P generation resulting in increased CAMP production comprises a novel regulatory mechanism of epithelial innate immune responses to external perturbations, pointing to a new therapeutic approach to enhance antimicrobial defense.

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

Cited by 59 publications

References 38 publications

Regulatory Role for the Profilaggrin N-Terminal Domain in Epidermal Homeostasis

Regulatory Role for the Profilaggrin N-Terminal Domain in Epidermal Homeostasis

Mechanosensitive ATP release from hemichannels and Ca2+ influx through TRPC6 accelerate wound closure in keratinocytes

A Novel Role of a Lipid Species, Sphingosine-1-Phosphate, in Epithelial Innate Immunity

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