Transcriptional coactivator with PDZ-binding motif stimulates epidermal regeneration via induction of amphiregulin expression after ultraviolet damage

Highlights

• TAZ is induced during epidermal regeneration in vivo.

• Keratinocyte-specific TAZ knockout delays epidermal regeneration.

• TAZ stimulates EGFR signaling with induction of EGFR ligand AREG after UVB exposure.

Abstract

Ultraviolet (UV) irradiation induces the proliferation and differentiation of keratinocytes in the basal layer of the epidermis, which increases epidermal thickness in skin regeneration. However, the mechanism underlying this phenomenon is not yet known in detail. In this study, we aimed to demonstrate that the transcriptional coactivator with PDZ-binding motif (TAZ) stimulates epidermal regeneration by increasing keratinocyte proliferation. During epidermal regeneration, TAZ is localized in the nucleus of keratinocytes of the basal layer and stimulates epidermal growth factor receptor (EGFR) signaling. TAZ depletion in keratinocytes decreased EGFR signaling activation, which delays epidermal regeneration. Interestingly, TAZ stimulated the transcription of amphiregulin (AREG), a ligand of EGFR, through TEAD-mediated transcriptional activation. Together, these results show that TAZ stimulates EGFR signaling through AREG induction, suggesting that it plays an important role in epidermal regeneration.

Introduction

The skin corresponds to the surface of our body and is organized in two major layers, epidermis and dermis. The epidermis, derived from the ectoderm, forms the outermost layer and provides a protective barrier from harmful environmental factors, such as infectious pathogens, ultraviolet (UV) irradiation, wounds, and chemicals [[1], [2], [3]]. Epidermal stem cells, which are keratinocytes in the basal layer of the epidermis, rapidly divide and differentiate as they migrate from the basement membrane to the surface of the skin, undergoing enucleation and cytokeratin accumulation and forming tight junctions [4,5]. This tightly formed epidermis also provides an effective physical barrier that helps block UV radiation from penetrating the skin through the accumulation of the melanin pigment in keratinocytes [6].

UV irradiation through sunlight exposure causes various skin diseases, such as inflammation, photoaging, and even cancer [7]. The shorter wavelength UVB (280–315 nm) contains highly energetic photons and penetrates the outermost layers of the skin, causing skin burning and, in severe cases, blistering. UVB radiation, upon absorption by cells, produces reactive oxygen species and causes DNA modifications, which in turn can lead to mutations or carcinogenesis [8,9]. UV stimulation causes a variety of cell surface receptors to send intracellular regenerative signals, such as those for MAP kinase (ERK, JNK and p38), JAK/STAT, and protein kinase-C pathways [[9], [10], [11], [12], [13], [14], [15], [16]]. In particular, the activation of the epidermal growth factor receptor (EGFR) by UVB irradiation plays a critical role in mediating the survival and proliferation of keratinocytes. Abnormal activation of EGFR can cause skin carcinogenesis; therefore, it is essential to understand the operation of the EGFR signaling after UVB irradiation in detail [17,18].

There are several ligands of EGFR, such as EGF and heparin-binding EGF-like growth factor (HB-EGF), which are abundantly produced in epidermal keratinocytes [19,20]. Among them, amphiregulin (AREG) is remarkably expressed in normal human skin epidermis and cultured keratinocytes, and its expression greatly increases in psoriatic epidermis [21,22]. Upon UVB irradiation, ADAM17 mediates the ectodomain shedding and liberation of AREG, which activates EGFR and, consequently, intracellular signal transduction [23]. These observations indicate that EGFR activity induced by AREG is important for keratinocyte proliferation and epidermal regeneration.

Transcriptional coactivator with PDZ-binding motif (TAZ), an effector of the hippo pathway, not only regulates the differentiation of specific cells, but also participates in tissue regeneration [[24], [25], [26]]. TAZ stimulates the expression of connective tissue growth factor (CTGF), cysteine-rich angiogenesis inducer 61 (Cyr61), and AREG, all of which regulate cell proliferation and migration [27,28]. However, the effects of TAZ on epidermal regeneration and the underlying mechanisms are largely unknown.

In this study, we investigated the role of TAZ in epidermal regeneration and observed that TAZ stimulates epidermal regeneration by promoting keratinocyte proliferation through AREG induction.