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

Ann E. Collier, Ronald Wek, Dan Spandau

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

This study delineates the mechanisms by which UVB regulates protein synthesis in human keratinocytes and the importance of translational control in cell survival. Translation initiation is regulated by phosphorylation of eukaryotic initiation factor 2 (eIF2-P) that causes decreased global protein synthesis coincident with enhanced translation of selected stress-related transcripts, such as activating transcription factor 4 (ATF4). ATF4 is a transcriptional activator of the integrated stress response (ISR) that has cytoprotective functions as well as apoptotic signals through the downstream transcriptional regulator C/EBP homologous protein (CHOP; GADD153/DDIT3). We determined that UVB irradiation is a potent inducer of eIF2-P in keratinocytes, leading to decreased levels of translation initiation. However, expression of ATF4 or CHOP was not induced by UVB as compared with traditional ISR activators. The rationale for this discordant response is that ATF4 mRNA is reduced by UVB, and despite its ability to be preferentially translated, there are diminished levels of available transcript. Forced expression of ATF4 and CHOP protein before UVB irradiation significantly enhanced apoptosis, suggesting that this portion of the ISR is deleterious in keratinocytes following UVB. Inhibition of eIF2-P and translational control reduced viability following UVB that was alleviated by cycloheximide (CHX), indicating that translation repression through eIF2-P is central to keratinocyte survival.

Original languageEnglish (US)
Pages (from-to)2502-2511
Number of pages10
JournalJournal of Investigative Dermatology
Volume135
Issue number10
DOIs
StatePublished - Oct 14 2015

Fingerprint

Activating Transcription Factor 4
Keratinocytes
Transcription Factor CHOP
Phosphotransferases
Apoptosis
Eukaryotic Initiation Factor-2
Irradiation
Phosphorylation
Proteins
Cycloheximide
Cell Survival
Cells
Messenger RNA

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

@article{1920c7720c0d4d6d90cbb001e2a932dc,
title = "Translational Repression Protects Human Keratinocytes from UVB-Induced Apoptosis through a Discordant eIF2 Kinase Stress Response",
abstract = "This study delineates the mechanisms by which UVB regulates protein synthesis in human keratinocytes and the importance of translational control in cell survival. Translation initiation is regulated by phosphorylation of eukaryotic initiation factor 2 (eIF2-P) that causes decreased global protein synthesis coincident with enhanced translation of selected stress-related transcripts, such as activating transcription factor 4 (ATF4). ATF4 is a transcriptional activator of the integrated stress response (ISR) that has cytoprotective functions as well as apoptotic signals through the downstream transcriptional regulator C/EBP homologous protein (CHOP; GADD153/DDIT3). We determined that UVB irradiation is a potent inducer of eIF2-P in keratinocytes, leading to decreased levels of translation initiation. However, expression of ATF4 or CHOP was not induced by UVB as compared with traditional ISR activators. The rationale for this discordant response is that ATF4 mRNA is reduced by UVB, and despite its ability to be preferentially translated, there are diminished levels of available transcript. Forced expression of ATF4 and CHOP protein before UVB irradiation significantly enhanced apoptosis, suggesting that this portion of the ISR is deleterious in keratinocytes following UVB. Inhibition of eIF2-P and translational control reduced viability following UVB that was alleviated by cycloheximide (CHX), indicating that translation repression through eIF2-P is central to keratinocyte survival.",
author = "Collier, {Ann E.} and Ronald Wek and Dan Spandau",
year = "2015",
month = "10",
day = "14",
doi = "10.1038/jid.2015.177",
language = "English (US)",
volume = "135",
pages = "2502--2511",
journal = "Journal of Investigative Dermatology",
issn = "0022-202X",
publisher = "Nature Publishing Group",
number = "10",

}

TY - JOUR

T1 - Translational Repression Protects Human Keratinocytes from UVB-Induced Apoptosis through a Discordant eIF2 Kinase Stress Response

AU - Collier, Ann E.

AU - Wek, Ronald

AU - Spandau, Dan

PY - 2015/10/14

Y1 - 2015/10/14

N2 - This study delineates the mechanisms by which UVB regulates protein synthesis in human keratinocytes and the importance of translational control in cell survival. Translation initiation is regulated by phosphorylation of eukaryotic initiation factor 2 (eIF2-P) that causes decreased global protein synthesis coincident with enhanced translation of selected stress-related transcripts, such as activating transcription factor 4 (ATF4). ATF4 is a transcriptional activator of the integrated stress response (ISR) that has cytoprotective functions as well as apoptotic signals through the downstream transcriptional regulator C/EBP homologous protein (CHOP; GADD153/DDIT3). We determined that UVB irradiation is a potent inducer of eIF2-P in keratinocytes, leading to decreased levels of translation initiation. However, expression of ATF4 or CHOP was not induced by UVB as compared with traditional ISR activators. The rationale for this discordant response is that ATF4 mRNA is reduced by UVB, and despite its ability to be preferentially translated, there are diminished levels of available transcript. Forced expression of ATF4 and CHOP protein before UVB irradiation significantly enhanced apoptosis, suggesting that this portion of the ISR is deleterious in keratinocytes following UVB. Inhibition of eIF2-P and translational control reduced viability following UVB that was alleviated by cycloheximide (CHX), indicating that translation repression through eIF2-P is central to keratinocyte survival.

AB - This study delineates the mechanisms by which UVB regulates protein synthesis in human keratinocytes and the importance of translational control in cell survival. Translation initiation is regulated by phosphorylation of eukaryotic initiation factor 2 (eIF2-P) that causes decreased global protein synthesis coincident with enhanced translation of selected stress-related transcripts, such as activating transcription factor 4 (ATF4). ATF4 is a transcriptional activator of the integrated stress response (ISR) that has cytoprotective functions as well as apoptotic signals through the downstream transcriptional regulator C/EBP homologous protein (CHOP; GADD153/DDIT3). We determined that UVB irradiation is a potent inducer of eIF2-P in keratinocytes, leading to decreased levels of translation initiation. However, expression of ATF4 or CHOP was not induced by UVB as compared with traditional ISR activators. The rationale for this discordant response is that ATF4 mRNA is reduced by UVB, and despite its ability to be preferentially translated, there are diminished levels of available transcript. Forced expression of ATF4 and CHOP protein before UVB irradiation significantly enhanced apoptosis, suggesting that this portion of the ISR is deleterious in keratinocytes following UVB. Inhibition of eIF2-P and translational control reduced viability following UVB that was alleviated by cycloheximide (CHX), indicating that translation repression through eIF2-P is central to keratinocyte survival.

UR - http://www.scopus.com/inward/record.url?scp=84941416315&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941416315&partnerID=8YFLogxK

U2 - 10.1038/jid.2015.177

DO - 10.1038/jid.2015.177

M3 - Article

C2 - 25950825

AN - SCOPUS:84941416315

VL - 135

SP - 2502

EP - 2511

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

IS - 10

ER -