RESUMO
The v-ATPase is a fundamental eukaryotic enzyme that is central to cellular homeostasis. Although its impact on key metabolic regulators such as TORC1 is well documented, our knowledge of mechanisms that regulate v-ATPase activity is limited. Here, we report that the Drosophila transcription factor Mitf is a master regulator of this holoenzyme. Mitf directly controls transcription of all 15 v-ATPase components through M-box cis-sites and this coordinated regulation affects holoenzyme activity in vivo. In addition, through the v-ATPase, Mitf promotes the activity of TORC1, which in turn negatively regulates Mitf. We provide evidence that Mitf, v-ATPase and TORC1 form a negative regulatory loop that maintains each of these important metabolic regulators in relative balance. Interestingly, direct regulation of v-ATPase genes by human MITF also occurs in cells of the melanocytic lineage, showing mechanistic conservation in the regulation of the v-ATPase by MITF family proteins in fly and mammals. Collectively, this evidence points to an ancient module comprising Mitf, v-ATPase and TORC1 that serves as a dynamic modulator of metabolism for cellular homeostasis.
Assuntos
Proteínas de Drosophila/metabolismo , Fator de Transcrição Associado à Microftalmia/metabolismo , Fatores de Transcrição/metabolismo , ATPases Vacuolares Próton-Translocadoras/genética , Animais , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Drosophila , Ativação Enzimática , Homeostase/fisiologia , Humanos , Melanócitos/metabolismo , Melanoma/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno , Transcrição Gênica/genética , ATPases Vacuolares Próton-Translocadoras/metabolismoRESUMO
The G protein-coupled MC1R is expressed in melanocytes and has a pivotal role in human skin pigmentation, with reduced function in human genetic variants exhibiting a red hair phenotype and increased melanoma predisposition. Beyond its role in pigmentation, MC1R is increasingly recognized as promoting UV-induced DNA damage repair. Consequently, there is mounting interest in targeting MC1R for therapeutic benefit. However, whether MC1R expression is restricted to melanocytes or is more widely expressed remains a matter of debate. In this paper, we review MC1R function and highlight that unbiased analysis suggests that its expression is restricted to melanocytes, granulocytes, and the brain.