Melanin Transfer and Fate within Keratinocytes in Human Skin Pigmentation

Abstract

Human skin and hair pigmentation play important roles in social behavior but also in photoprotection from the harmful effects of ultraviolet light. The main pigments in mammalian skin, the melanins, are synthesized within specialized organelles called melanosomes in melanocytes, which sit at the basal layer of the epidermis and the hair bulb. The melanins are then transferred from melanocytes to keratinocytes, where they accumulate perinuclearly in membrane-bound organelles as a "cap" above the nucleus. The mechanism of transfer, the nature of the pigmented organelles within keratinocytes, and the mechanism governing their intracellular positioning are all debated and poorly understood, but likely play an important role in the photoprotective properties of melanin in the skin. Here, we detail our current understanding of these processes and present a guideline for future experimentation in this area.

Fig. 1.

Model of melanin transfer and the MC+ organelle in human skin keratinocytes. Four different models are proposed to explain the transfer of melanin from melanocytes to keratinocytes: (a) the melanocyte sheds a large vesicle that contains melanosomes and is internalized by the keratinocyte; (b) the keratinocyte employs cytophagocytosis to internalize a melanocyte dendrite or filopodium that contains multiple melanosomes; (c) the melanocyte emits by exocytosis the intraluminal content of melanosome, called the MC, and the MC is then internalized by the keratinocyte; and (d) tunneling nanotubes support the exchange of melanosomes from melanocytes to keratinocytes upon fusion of their plasma membranes (red and blue, respectively). While models a, b and d propose the transfer of intact melanosomes (limiting membrane in green), model c suggests that the pigmented transferred structure is a MC. The a, b, and c models suggest that the plasma membrane of the keratinocyte must be extensively remodeled by the dynamic rearrangement of actin filaments (red lines) in order to engulf melanin particles through a process of phagocytosis or macropinocytosis. These modes of internalization appear to be regulated by PAR-2 on the plasma membrane of the keratinocyte. Once MCs are endocytosed, they reside in a membrane-bound compartment (MC+ organelle; limiting membrane in blue) that is rapidly distributed to the perinuclear area where they establish close contacts with mitochondria and endoplasmic reticulum. This is likely mediated by centripetal dynein-dependent microtubule-based transport (arrows, Box 1). MC+ organelles bear lysosomal components (LAMP1, CD63; Box 2), but remain distinct from late endosomes/multivesicular bodies (MVBs) and lysosomes. MC+ organelles in darkly pigmented skin contain one MC, whereas those in lightly pigmented skin contain several MCs (Box 2). The main role of the MC+ organelles in keratinocytes is to support photoprotection of the genetic material that can occur through UV-dependent DNA damage, including CPDs (Box 3).