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J Invest Dermatol. 2017 Sep;137(9):1924-1934. doi: 10.1016/j.jid.2017.04.029. Epub 2017 May 17.

Human Keratinocyte Differentiation Requires Translational Control by the eIF2α Kinase GCN2.

Author information

1
Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
2
Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA. Electronic address: rwek@iu.edu.
3
Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana, USA. Electronic address: dspanda@iupui.edu.

Abstract

Appropriate and sequential differentiation of keratinocytes is essential for all functions of the human epidermis. Although transcriptional regulation has proven to be important for keratinocyte differentiation, little is known about the role of translational control. A key mechanism for modulating translation is through phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2). A family of different eIF2α kinases function in the integrative stress response to inhibit general protein synthesis coincident with preferential translation of select mRNAs that participate in stress alleviation. Here we demonstrate that translational control through eIF2α phosphorylation is required for normal keratinocyte differentiation. Analyses of polysome profiles revealed that key differentiation genes, including involucrin, are bound to heavy polysomes during differentiation, despite decreased general protein synthesis. Induced eIF2α phosphorylation by the general control nonderepressible 2 (GCN2) protein kinase facilitated translational control and differentiation-specific protein expression during keratinocyte differentiation. Furthermore, loss of GCN2 thwarted translational control, normal epidermal differentiation, and differentiation gene expression in organotypic skin culture. These findings underscore a previously unknown function for GCN2 phosphorylation of eIF2α and translational control in the formation of an intact human epidermis.

PMID:
28528168
PMCID:
PMC5873978
DOI:
10.1016/j.jid.2017.04.029
[Indexed for MEDLINE]
Free PMC Article

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