ZNF750 Regulates Skin Barrier Function by Driving Cornified Envelope and Lipid Processing Pathways.

The epidermis is a constantly renewing stratified epithelial tissue that provides essential protective barrier functions. The major barrier is located at the outermost layers of the epidermis, formed by terminally differentiated keratinocytes reinforced by proteins of their cornified envelope and sequestered intercellular lipids. Disruptions to epidermal differentiation characterize various skin disorders. ZNF750 is an epithelial transcription factor essential for in vitro keratinocyte differentiation, whose truncating mutation in humans causes autosomal dominant psoriasis-like skin disease. In this study, we utilized an epidermal-specific Znf750 conditional knockout mouse model to uncover the role ZNF750 plays in epidermal development. We show that deletion of Znf750 in the developing skin does not block epidermal differentiation completely, suggesting in vivo compensatory feedback mechanisms, although it does result in impaired barrier function and perinatal lethality. Molecular dissection revealed ultrastructural defects in the differentiated layers of the epidermis, accompanied by alterations in the expression of ZNF750-dependent genes encoding key cornified envelope precursor proteins and lipid-processing enzymes, including gene subsets known to be mutated in human skin diseases involving impaired barrier function. Together, our findings provide molecular insights into the pathogenesis of human skin disease by linking ZNF750 to a subset of epidermal differentiation genes involved in barrier formation pathways.

LeishIF4E-5 Is a Promastigote-Specific Cap-Binding Protein in Leishmania.

Leishmania parasites cycle between sand fly vectors and mammalian hosts, transforming from extracellular promastigotes that reside in the vectors' alimentary canal to obligatory intracellular non-motile amastigotes that are harbored by macrophages of the mammalian hosts. The transition between vector and host exposes them to a broad range of environmental conditions that induces a developmental program of gene expression, with translation regulation playing a key role. The Leishmania genome encodes six paralogs of the cap-binding protein eIF4E. All six isoforms show a relatively low degree of conservation with eIF4Es of other eukaryotes, as well as among themselves. This variability could suggest that they have been assigned discrete roles that could contribute to their survival under the changing environmental conditions. Here, we describe LeishIF4E-5, a LeishIF4E paralog. Despite the low sequence conservation observed between LeishIF4E-5 and other LeishIF4Es, the three aromatic residues in its cap-binding pocket are conserved, in accordance with its cap-binding activity. However, the cap-binding activity of LeishIF4E-5 is restricted to the promastigote life form and not observed in amastigotes. The overexpression of LeishIF4E-5 shows a decline in cell proliferation and an overall reduction in global translation. Immuno-cytochemical analysis shows that LeishIF4E-5 is localized in the cytoplasm, with a non-uniform distribution. Mass spectrometry analysis of proteins that co-purify with LeishIF4E-5 highlighted proteins involved in RNA metabolism, along with two LeishIF4G paralogs, LeishIF4G-1 and LeishIF4G-2. These vary in their conserved eIF4E binding motif, possibly suggesting that they can form different complexes.