Arginase-2, a miR-1299 target, enhances pigmentation in melasma by reducing melanosome degradation via senescence-induced autophagy inhibition.

Expression profiles revealed miR-1299 downregulation concomitant with arginase-2 (ARG2) upregulation in hyperpigmented skin of melasma patients. Opposite regulation of tyrosinase and PMEL17 by miR-1299 and inverse relationship between miR-1299 and ARG2 expression denoted a role of miR-1299 in pigmentation with ARG2 as a miR-1299 target. ARG2 overexpression or knock-down in keratinocytes, the main source of ARG2 in epidermis, positively regulated tyrosinase and PMEL17 protein levels, but not mRNA levels or melanosome transfer. ARG2 overexpression in keratinocytes reduced autophagy equivalent to 3-MA, an autophagy inhibitor which also increased tyrosinase and PMEL17 protein levels, whereas ARG2 knock-down induced opposite results. Autophagy inducer rapamycin reduced ARG2-increased tyrosinase and PMEL17 protein levels. Also, autophagy was reduced in late passage-induced senescent keratinocytes showing ARG2 upregulation. ARG2, but not 3-MA, stimulated keratinocyte senescence. These results suggest that ARG2 reduces autophagy in keratinocytes by stimulating cellular senescence, resulting in skin pigmentation by reducing degradation of transferred melanosomes.