Functional cell death, corneoptosis, requires temporally controlled intracellular acidification.

As the mammalian body’s largest organ, the skin is the first defense against a host of environmental insults. Specifically, the outermost layer of the skin, the stratum corneum (SC), provides much of the essential barrier function of the epidermis, protecting the body’s surface from mechanical force, water loss, pathogens, toxins, and allergens (1). Epithelial cells of the skin, called keratinocytes, undergo various sequential stages of differentiation on their way to this outermost layer of the stratified epithelium. Proliferative keratinocytes originate in the stratum basale (SB) and first differentiate into the stratum spinosum (SS) layers (2, 3). They continue differentiating, forming the three layers of the stratum granulosum (SG3, SG2, and SG1), with a tight junction-mediated barrier forming in SG2. Finally, SG1 cells undergo a very specific kind of cell death, beginning the process of cornification and leading to the formation of the SC, layers of dead keratinocytes and the functional barrier of the skin (4, 5). This differentiation step is perhaps one of the most interesting, as the remnants of this mode of cell death (corneocytes) remain functional and essential to the skin barrier. This complex form of keratinocyte death involves degradation of membraneless organelles called keratohyalin granules (KHGs), formation of the cornified envelope which replaces the plasma membrane, and degradation of the nucleus (Fig. 1) (1, 4). However, the exact cellular and molecular mechanisms underpinning this unique process of cell death are still not fully understood. Matsui et al. (6) combine elegant in vivo and in … [↵][1]1To whom correspondence may be addressed. Email: jessica.l.moore{at}yale.edu or valentina.greco{at}yale.edu. [1]: #xref-corresp-1-1