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 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.
Council for Scientific and Industrial Research - Institute of Genomics and Integrative Biology, Delhi 110007, India.
Vivek T
VT
Natarajan
Parul
P
Ganju
Archana
A
Singh
Vinaya
V
Vijayan
Kritika
K
Kirty
Shalini
S
Yadav
Shraddha
S
Puntambekar
Sonali
S
Bajaj
Prachi P
PP
Dani
Hemanta K
HK
Kar
Chetan J
CJ
Gadgil
Krishnamurthy
K
Natarajan
Rajni
R
Rani
Rajesh S
RS
Gokhale
D000818:Animals; D045744:Cell Line, Tumor; D007371:Interferon-gamma / Q000378:metabolism*; D008544:Melanocytes / Q000166:cytology*; D020460:Melanosomes / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D015398:Signal Transduction; D012880:Skin Pigmentation; D014158:Transcription, Genetic
D007371:Interferon-gamma
detanning; gene regulation; interferon; melanin