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The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wound healing via coordination of reactive oxygen species and amino acids.

ABSTRACT: Healing of cutaneous wounds requires the collective migration of epithelial keratinocytes to seal the wound bed from the environment. However, the signaling events that coordinate this collective migration are unclear. In this report, we address the role of phosphorylation of eukaryotic initiation factor 2 (eIF2) and attendant gene expression during wound healing. Wounding of human keratinocyte monolayers in vitro led to the rapid activation of the eIF2 kinase GCN2. We determined that deletion or pharmacological inhibition of GCN2 significantly delayed collective cell migration and wound closure. Global transcriptomic, biochemical, and cellular analyses indicated that GCN2 is necessary for maintenance of intracellular free amino acids, particularly cysteine, as well as coordination of RAC1-GTP-driven reactive oxygen species (ROS) generation, lamellipodia formation, and focal adhesion dynamics following keratinocyte wounding. In vivo experiments using mice deficient for GCN2 validated the role of the eIF2 kinase during wound healing in intact skin. These results indicate that GCN2 is critical for appropriate induction of collective cell migration and plays a critical role in coordinating the re-epithelialization of cutaneous wounds.

SUBMITTER: Miles RR

PROVIDER: S-EPMC8554533 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wounding by proper coordination of reactive oxygen species and amino acids

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The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wounding by proper coordination of reactive oxygen species and amino acids

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Project description:The skin is the largest and a remarkably plastic organ that serves as a protective barrier against environmental stimuli and injuries throughout life. Skin injuries are serious health problems, and wound healing is a critical process to replace devitalized cellular and tissue structures. Although some endogenous opioids are known to be involved in the modulation of wound healing, it remains to be determined whether the ?-neoendorphin (?-NEP), an endogenous opioid, has beneficial effects on wound repair in human keratinocyte. In this study, we found that ?-NEP accelerated wound repair through activation of mitogen-activated protein kinase (MAPK)/Erk1/2 signaling pathways in human keratinocytes. Moreover, the wound healing effect of ?-NEP is mainly through the acceleration of keratinocyte migration without affecting cell proliferation. Therefore, our studies reveal that ?-NEP plays an important role in the regulation of wound repair and suggest a therapeutic strategy to promote wound healing using ?-NEP.

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Project description:Reepithelialization during cutaneous wound healing involves numerous signals that result in basal keratinocyte activation, spreading, and migration, all linked to a loosening of cell-cell adhesion structures. The transcription factor Slug is required for this process, and EGF treatment of human keratinocytes induced activating phosphorylation of Erk5 that coincides with slug transcription. Accordingly, ectopic activation of Erk5 led to increased Slug mRNA levels and faster wound healing, whereas keratinocyte migration was totally blocked by Erk5 pathway inhibition. Expression of a shRNA specific for Erk5 strongly diminished Erk5 levels in keratinocytes and significantly decreased their motility response to EGF, along with induction of Slug expression. These Erk5-deprived keratinocytes showed an altered, more compact morphology, along with disruption of desmosome organization. Accordingly, they displayed an altered ability to form cell aggregates. These results implicate a novel EGFR/Erk5/Slug pathway in the control of cytoskeleton organization and cell motility in keratinocytes treated with EGF.

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