Structural Organization and Regulation of the Small Proline-rich Family of Cornified Envelope Precursors Suggest a Role in Adaptive Barrier Function

Abstract

The protective barrier provided by stratified squamous epithelia relies on the cornified cell envelope (CE), a structure synthesized at late stages of keratinocyte differentiation. It is composed of structural proteins, including involucrin, loricrin, and the small proline-rich (SPRR) proteins, all encoded by genes localized at human chromosome 1q21. The genetic characterization of the SPRR locus reveals that the various members of this multigene family can be classified into two distinct groups with separate evolutionary histories. Whereas group 1 genes have diverged in protein structure and are composed of three different classes (SPRR1 (2؋), SPRR3, and SPRR4), an active process of gene conversion has counteracted diversification of the protein sequences of group 2 genes (SPRR2 class, seven genes). Contrasting with this homogenization process, all individual members of the SPRR gene family show specific in vivo and in vitro expression patterns and react selectively to UV irradiation. Apparently, creation of regulatory rather than structural diversity has been the driving force behind the evolution of the SPRR gene family. Differential regulation of highly homologous genes underlines the importance of SPRR protein dosage in providing optimal barrier function to different epithelia, while allowing adaptation to diverse external insults.

Gene expression pattern and hormonal regulation of Small Proline-Rich Protein 2 family members in the female mouse reproductive system during the estrous cycle and pregnancy

“…However, many other conserved binding sites are not commonly dispersed, like Ets and kruppel binding sites [10]. The unique combination of these regulatory sites allows fine adjustment of each sprr2 gene expression in response to the same or different signals [14,20]. Unlike that in the skin, the transcriptional regulation of sprr2 members in the reproductive organs is under the control of cycling sex hormones as indicated in the present study.…”

“…Interestingly, sprr mRNA and the corresponding proteins were recently found in the uterine epithelium and ovary where only simple epithelium or simple epithelium-like cells exist. Specifically, the human ovary expresses sprr1, 2 and 3, whereas human and mouse uteri express sprr2 but not sprr 1 and 3 [13,14]. Therefore, the question of the novel role of sprr2 proteins in the reproductive process has arisen.…”

Small proline-rich proteins 2 are noncoordinately upregulated by IL-6/STAT3 signaling after bile duct ligation

“…Therefore, regulatory diversity appears to have been more important than diversification of protein structure during evolution of these genes. 2 This implies that control of SPRR protein dosage is of major functional importance. 2 As with other members of the EDC, 5 SPRR genes can be coordinately regulated as part of the EDC (ie high expression of most EDC genes, as in papillomas, or very low expression of most genes, as in newborn skin), or noncoordinately regulated (eg high expression of the SPRR2 genes) to enable selective modification of a particular barrier.…”

“…1,4 The SPRR genes encode for a series of highly homologous proteins that are critical components of the CE, an effective barrier against the environment. 2,3,[5][6][7] Many members of the SPRR protein family differ by only one to three amino acids. Therefore, regulatory diversity appears to have been more important than diversification of protein structure during evolution of these genes.…”

“…The EDC is a cluster of more than 50 genes located on chromosome 1q21 [1][2][3] whose products are involved in terminal differentiation of the human epidermis, including precursors of the cornified cell envelope (CE) (loricrin, involcrin, and SPRR), intermediate filament-associated proteins, and the S100 family of calcium-binding proteins. 1,4 The SPRR genes encode for a series of highly homologous proteins that are critical components of the CE, an effective barrier against the environment.…”