THE MULTIFUNCTIONAL PROTEIN E4F1 REGULATES MELANOCYTIC FUNCTIONS IN MICE THROUGH PROTEIN TRANSLATION AND MITF EXPRESSION

Abstract

The multifunctional protein E4 transcription factor 1 (E4F1) is an essential regulator of skin homeostasis, playing a critical role in epidermal stem cell maintenance and keratinocyte differentiation. However, the functions of E4F1 in other skin cell type remain poorly investigated. Here, we describe its role in melanogenesis, the physiological process for synthesis of melanin pigments. Using genetically engineered mouse models that enabled conditional inactivation of E4f1 specifically in melanocytes, we demonstrated that E4f1 loss induces severe pigmentation defects without affecting melanocyte survival nor differentiation. At the molecular level, E4f1 depletion reduces the expression of its direct transcriptional target genes involved in protein translation, including Elp3 and Eef1g, leading to translation alterations and consequently the induction of the Integrated Stress Response (ISR). This response resulted in microphthalmia-associated transcription factor (MITF) downregulation, inducing a decrease in the expression of enzymes involved in melanin synthesis. Consistent with these findings, Elp3 or Eef1g depletion recapitulated the decrease in MITF levels in vitro, and pharmacological inhibition of ISR partially rescued melanin content in vivo, confirming a key role of the E4F1-protein translation-ISR cascade in melanogenesis. Together, our data identify E4F1-associated translation functions as a key regulator of the melanocytic lineage.