IFN-γ signaling maintains skin pigmentation homeostasis through regulation of melanosome maturation

Cellular homeostasis is an outcome of complex interacting processes with nonlinear feedbacks that can span distinct spatial and temporal dimensions. Skin tanning is one such dynamic response that maintains genome integrity of epidermal cells. Although pathways underlying hyperpigmentation cascade ar...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2014-02, Vol.111 (6), p.2301-2306
Main Authors: Natarajan, Vivek T., Ganju, Parul, Singh, Archana, Vijayan, Vinaya, Kirty, Kritika, Yadav, Shalini, Puntambekar, Shraddha, Bajaj, Sonali, Dani, Prachi P., Kar, Hemanta K., Gadgil, Chetan J., Natarajan, Krishnamurthy, Rani, Rajni, Gokhale, Rajesh S.
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Cell Line, Tumor
Cultured cells
Genes
Government regulation
Hypopigmentation
Interferon-gamma - metabolism
Melanin
Melanocytes
Melanocytes - cytology
Melanosomes
Melanosomes - metabolism
Melanosomes - ultrastructure
Mice
Mice, Knockout
Microscopy, Electron, Transmission
Pigmentation
Signal Transduction
Skin
Skin Pigmentation
Stem cells
Transcription, Genetic
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Summary:Cellular homeostasis is an outcome of complex interacting processes with nonlinear feedbacks that can span distinct spatial and temporal dimensions. Skin tanning is one such dynamic response that maintains genome integrity of epidermal cells. Although pathways underlying hyperpigmentation cascade are recognized, negative feedback regulatory loops that can dampen the activated melanogenesis process are not completely understood. In this study, we delineate a regulatory role of IFN-γ in skin pigmentation biology. We show that IFN-γ signaling impedes maturation of the key organelle melanosome by concerted regulation of several pigmentation genes. Withdrawal of IFN-γ signal spontaneously restores normal cellular programming. This effect in melanocytes is mediated by IFN regulatory factor-1 and is not dependent on the central regulator microphthalmia-associated transcription factor. Chronic IFN-γ signaling shows a clear hypopigmentation phenotype in both mouse and human skin. Interestingly, IFN-γ KO mice display a delayed recovery response to restore basal state of epidermal pigmentation after UV-induced tanning. Together, our studies delineate a new spatiotemporal role of the IFN-γ signaling network in skin pigmentation homeostasis, which could have implications in various cutaneous depigmentary and malignant disorders.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1304988111