Tian Xiaoyu, Wang Hanyu, Liu Song, Liu Wei, Zhang Kaiyue, Gao Xiaohan, Li Qingchao, Zhao Huijie, Zhang Liangran, Liu Peiwei, Liu Min, Wang Youjun, Zhu Xueliang, Cui Rutao, Zhou Jun
Center for Cell Structure and Function, Shandong Provincial Key Laboratory of Animal Resistance Biology, College of Life Sciences, Shandong Normal University, Jinan, China.
Department of Pediatric Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
PLoS Biol. 2024 Dec 2;22(12):e3002940. doi: 10.1371/journal.pbio.3002940. eCollection 2024 Dec.
Production of melanin pigments is a protective mechanism of the skin against ultraviolet (UV)-induced damage and carcinogenesis. However, the molecular basis for melanogenesis is still poorly understood. Herein, we demonstrate a critical interplay between the primary cilium and the melanocortin 1 receptor (MC1R) signaling. Our data show that UV and α-melanocyte-stimulating hormone (α-MSH) trigger cilium formation in human melanocytes and melanoma cells. Deficiency of MC1R or the presence of its red hair color (RHC) variations significantly attenuates the UV/α-MSH-induced ciliogenesis. Further investigation reveals that MC1R enters the cilium upon UV/α-MSH stimulation, which is facilitated by the interaction of MC1R with the BBSome and the palmitoylation of MC1R. MC1R interacts with the BBSome through the second and third intercellular loops, which contain the common RHC variant alleles (R151C and R160W). These RHC variants of MC1R exhibit attenuated ciliary localization, and enforced ciliary localization of these variants elevates melanogenesis. Ciliary MC1R triggers a sustained cAMP signaling and selectively stimulates Sox9, which appears to up-regulate melanogenesis-related genes as the transcriptional cofactor for MITF. These findings reveal a previously unrecognized nexus between MC1R and cilia and suggest an important mechanism for RHC variant-related pigmentary defects.
黑色素的产生是皮肤抵御紫外线（UV）诱导损伤和致癌作用的一种保护机制。然而，黑色素生成的分子基础仍知之甚少。在此，我们证明了初级纤毛与黑皮质素1受体（MC1R）信号传导之间的关键相互作用。我们的数据表明，紫外线和α-黑素细胞刺激激素（α-MSH）可触发人黑素细胞和黑色素瘤细胞中的纤毛形成。MC1R的缺乏或其红发颜色（RHC）变异的存在会显著减弱紫外线/α-MSH诱导的纤毛发生。进一步研究发现，在紫外线/α-MSH刺激下，MC1R进入纤毛，这是由MC1R与BBSome的相互作用以及MC1R的棕榈酰化促进的。MC1R通过包含常见RHC变异等位基因（R151C和R160W）的第二和第三细胞内环与BBSome相互作用。这些MC1R的RHC变异体表现出减弱的纤毛定位，而强制这些变异体的纤毛定位可提高黑色素生成。纤毛MC1R触发持续的cAMP信号传导，并选择性地刺激Sox9，Sox9似乎作为MITF的转录辅因子上调黑色素生成相关基因。这些发现揭示了MC1R与纤毛之间以前未被认识的联系，并提示了RHC变异相关色素沉着缺陷的重要机制。
