Caspase-14-like Proteases: An Epidermal Caspase and Its Evolutionarily Ancient Relatives

TL;DR

This paper explores caspase-14-like proteases, focusing on their roles in skin function and evolution across amniotes.

Contribution

The paper provides a comprehensive review of the molecular and evolutionary characteristics of caspase-14-like proteases.

Findings

Caspase-14 is uniquely expressed in epithelial cells and is linked to skin barrier function.

Caspase-15 and -16 are evolutionarily older and have distinct structural features compared to caspase-14.

Mutations in the human CASP14 gene are associated with the skin disorder ichthyosis.

Abstract

Caspases are a family of cysteine-dependent aspartate-directed proteases implicated in programmed cell death. Humans have eleven proteolytically active caspases, namely caspase-1 through -10 and caspase-14. The latter is expressed exclusively in epithelial cells and constitutively resides in its active form in the cornified layer of the human epidermis. Molecular phylogenetics has revealed that caspase-14 belongs to a subfamily of caspases, which also includes caspase-15 and -16. The latter are evolutionarily more ancient than caspase-14 and have been lost in the phylogenetic lineage leading to humans. Here, we review the molecular properties, the species distributions, and the biological roles of caspase-14-like proteases in amniotes. In contrast to the prodomain-less caspase-14, caspase-15 contains a prodomain that is predicted to assume a pyrin fold, and caspase-16 features a prodomain with unique sequence similarity to the catalytic domain. Gene knockout in mice, evolutionary gene loss in aquatic mammals and the association of human CASP14 mutations with ichthyosis indicate that caspase-14 is associated with the barrier function of mammalian skin. Caspase-15 is able to induce apoptosis in cell culture, but its role in vivo and the role of caspase-16 are currently unknown. We propose directions for research to further characterize caspase-14-like proteases.

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