Translational Repression Protects Human Keratinocytes from UVB-Induced Apoptosis through a Discordant eIF2 Kinase...

Area of Science:

• Molecular Biology
• Cell Biology
• Dermatology

Background:

• UVB irradiation impacts protein synthesis in human keratinocytes.
• Translational control, particularly eukaryotic initiation factor 2 phosphorylation (eIF2-P), influences stress responses.
• The integrated stress response (ISR) involves factors like activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), with dual roles in cell fate.

Purpose of the Study:

• To investigate the mechanisms of UVB-induced protein synthesis regulation in keratinocytes.
• To determine the role of translational control and the ISR in keratinocyte survival following UVB exposure.
• To elucidate the specific contributions of ATF4 and CHOP to UVB-induced apoptosis or cytoprotection.

Main Methods:

• Exposure of human keratinocytes to UVB irradiation.
• Analysis of protein synthesis levels and translational initiation factors (eIF2-P).
• Assessment of ATF4 and CHOP expression and their impact on apoptosis, including forced expression studies and inhibition of translational control.

Main Results:

• UVB irradiation potently induces eIF2-P in keratinocytes, decreasing global protein synthesis.
• UVB does not induce ATF4 or CHOP expression, unlike traditional ISR activators, due to reduced ATF4 mRNA levels.
• Forced expression of ATF4/CHOP increased UVB-induced apoptosis, while inhibiting eIF2-P reduced keratinocyte viability, which was rescued by cycloheximide (CHX).

Conclusions:

• UVB-induced translational repression via eIF2-P is a critical cytoprotective mechanism in keratinocytes.
• The pro-apoptotic arm of the ISR (ATF4/CHOP) is detrimental to keratinocytes under UVB stress.
• Targeting translational control pathways offers a potential strategy for enhancing skin cell survival against UV damage.