Stress-induced RNASET2 overexpression mediates melanocyte apoptosis via the TRAF2 pathway in vitro

Q Wang,X Zhang,Q Chen,M Jiang,T Li,Y Ma,L Xiang,J Wu

doi:10.1038/cddis.2013.539

Abstract

The recent genome-wide association study identified a link between vitiligo and genetic variants in the ribonuclease T2 (RNASET2) gene; however, the functional roles of RNASET2 in vitiligo pathogenesis or in melanocyte apoptosis have yet to be determined. The current study was designed to investigate the vitiligo-related expression pattern of RNASET2 and its molecular function involving apoptosis-related signaling proteins and pathways. The results showed overexpression of RNASET2 in epidermis specimens from 40 vitiligo patients compared with that from matched healthy controls. In addition, in vitro analyses indicated that overexpression of RNASET2 was inducible in cultured primary human melanocytes and keratinocytes by stress conditions, that is, exposure to UV irradiation, hydrogen peroxide, and inflammatory factors, respectively, and led to increased cell apoptosis via the tumor necrosis factor receptor-associated factor 2 (TRAF2)–caspases pathway through the physical interaction of RNASET2 with TRAF2. Thus, RNASET2 may contribute to vitiligo pathogenesis by inhibiting TRAF2 expression and, as such, RNASET2 may represent a potential therapeutic target of vitiligo.

Highlights

As such, perturbations in their expression profiles have been associated with various pathological conditions, including cancers and autoimmune diseases
In silico analysis of the ribonuclease T2 (RNASET2) amino acid sequence identified a putative binding motif for the tumor necrosis factor receptor-associated factor 2 (TRAF2),[10] which has recently been recognized as a threshold determinant factor of apoptosis through its ubiquitin ligase activities acting on caspase-8.11 This finding becomes intriguing when considered in the context of the clinical and laboratory histology data of vitiligo-affected tissues that have demonstrated apoptosis, rather than cell death, is responsible for the melanocyte loss.[12]
We postulated that the interaction of TRAF2 and RNASET2 may contribute to vitiligo pathogenesis in humans, possibly by perturbing the apoptosis mechanism in the involved cells

Summary

Introduction

Perturbations in their expression profiles have been associated with various pathological conditions, including cancers and autoimmune diseases. Studies to determine the role of RNASET2 in cancers have elucidated its suppressive effects – independent of its nuclease activity – on cell growth and metastatic potential, both in vitro and in vivo.[5,6,7] To date, RNASET2 is the only member of the Rh/T2/S family of acidic hydrolases identified in humans,[8] but more recent studies of the RNASET2 ortholog in Saccharomyces cerevisiae, Rny[1], have demonstrated a similar function, in that Rny[1] can mediate inhibition of cell growth in response to oxidative stress conditions and that this activity is independent of the enzyme’s catalytic activity.[9]. We describe our study using in vitro approaches to determine the vitiligo-related expression pattern of RNASET2 using patient specimens and healthy tissues from matched control donors, and to uncover the molecular mechanism involving RNASET2 mediating the TRAF2–caspase signaling pathway of apoptosis using cultured primary human epidermal melanocytes (HEMs) and keratinocytes (HEKs)

Methods

Results

Conclusion