HDAC4 protects cells from ER stress induced apoptosis through interaction with ATF4

Pengfei Zhang; Qiao Sun; Chenyang Zhao; Shukuan Ling; Qi Li; Yan-Zhong Chang; Yingxian Li

doi:10.1016/j.cellsig.2013.11.026

HDAC4 protects cells from ER stress induced apoptosis through interaction with ATF4

Cell Signal. 2014 Mar;26(3):556-63. doi: 10.1016/j.cellsig.2013.11.026. Epub 2013 Dec 2.

Authors

Pengfei Zhang¹, Qiao Sun², Chenyang Zhao³, Shukuan Ling², Qi Li², Yan-Zhong Chang⁴, Yingxian Li⁵

Affiliations

¹ Key Lab of Physiology, Biochemistry & Molecular Biology of Hebei Province, Hebei Normal University, Shijiazhuang 050024, China; State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China.
² State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China.
³ Key Lab of Physiology, Biochemistry & Molecular Biology of Hebei Province, Hebei Normal University, Shijiazhuang 050024, China.
⁴ Key Lab of Physiology, Biochemistry & Molecular Biology of Hebei Province, Hebei Normal University, Shijiazhuang 050024, China. Electronic address: chang7676@163.com.
⁵ State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing 100094, China. Electronic address: yingxianli@aliyun.com.

PMID: 24308964
DOI: 10.1016/j.cellsig.2013.11.026

Abstract

Histone deacetylase 4 (HDAC4) is involved in the regulation of many fundamental cell processes such as proliferation, differentiation, and survival via the modification of their substrates or protein-protein interactions. In this study, we found that HDAC4 could be upregulated under ER stress. There exists a direct interaction between HDAC4 and activating transcription factor 4 (ATF4). In vitro, overexpression of HDAC4 caused the retention of ATF4 in cytoplasm and inhibition of ATF4 transcriptional activity. ER stress could promote cell apoptosis through the upregulation of ATF4 levels and its target genes such as CHOP and TRB3. This effect was exacerbated by downregulation of HDAC4 levels. These results demonstrated that HDAC4 played an important role in the regulation of ER stress-induced apoptosis through interacting with ATF4 and inhibiting its transcriptional activity.

Keywords: ATF4; Cell apoptosis; Endoplasmic reticulum stress; HDAC4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3 Cells
Activating Transcription Factor 4 / biosynthesis
Activating Transcription Factor 4 / genetics*
Activating Transcription Factor 4 / metabolism
Animals
Apoptosis / genetics*
Calcium-Transporting ATPases / antagonists & inhibitors
Cell Cycle Proteins / biosynthesis
Cell Line
Endoplasmic Reticulum / metabolism
Endoplasmic Reticulum Stress / drug effects
Endoplasmic Reticulum Stress / genetics*
Enzyme Inhibitors / pharmacology
Eukaryotic Initiation Factor-2 / metabolism
Glycosylation / drug effects
HEK293 Cells
Histone Deacetylases / biosynthesis
Histone Deacetylases / genetics*
Histone Deacetylases / metabolism
Humans
Mice
Phosphorylation
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / biosynthesis
RNA Interference
RNA, Small Interfering
Repressor Proteins / biosynthesis
Repressor Proteins / genetics*
Repressor Proteins / metabolism
Signal Transduction
Thapsigargin / pharmacology
Transcription Factor CHOP / biosynthesis
Transcription, Genetic / genetics
Transcriptional Activation / genetics
Up-Regulation
eIF-2 Kinase / biosynthesis
eIF-2 Kinase / metabolism

Substances

ATF4 protein, human
Cell Cycle Proteins
DDIT3 protein, human
Enzyme Inhibitors
Eukaryotic Initiation Factor-2
RNA, Small Interfering
Repressor Proteins
TRIB3 protein, human
Activating Transcription Factor 4
Transcription Factor CHOP
Thapsigargin
EIF2AK3 protein, human
Protein Serine-Threonine Kinases
eIF-2 Kinase
HDAC4 protein, human
Histone Deacetylases
Calcium-Transporting ATPases