Human Keratinocyte Differentiation Requires Translational Control by the eIF2α Kinase GCN2

Ann E. Collier, Ronald Wek, Dan Spandau

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1924-1934
Number of pages11
JournalJournal of Investigative Dermatology
Volume137
Issue number9
DOIs
StatePublished - Sep 1 2017

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Eukaryotic Initiation Factor-2
Keratinocytes
Phosphorylation
Polyribosomes
Epidermis
Proteins
Protein Biosynthesis
Protein Kinases
Phosphotransferases
Gene Expression
Skin
Gene expression
Genes
Messenger RNA

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Human Keratinocyte Differentiation Requires Translational Control by the eIF2α Kinase GCN2. / Collier, Ann E.; Wek, Ronald; Spandau, Dan.

In: Journal of Investigative Dermatology, Vol. 137, No. 9, 01.09.2017, p. 1924-1934.

Research output: Contribution to journalArticle

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