3 β-hydroxysteroid-Δ 24 reductase (DHCR24) protects neuronal cells from apoptotic cell death induced by endoplasmic reticulum (ER) stress.
3β-Hydroxysteroid-Δ24 reductase (DHCR24) is an endoplasmic reticulum (ER)-localized multifunctional enzyme that possesses anti-apoptotic and cholesterol-synthesizing activities. Accumulating evidence suggests that ER stress is involved in the pathogenesis of neurodegenerative disease. In this study, we investigated whether DHCR24 may function as a neuroprotective protein under ER stress. Neuroblastoma N2A cells were infected with adenovirus expressing myc-tagged DHCR24 (Ad-DHCR24) or lacZ (Ad-lacZ, serving as a control) and subjected to ER-stress, induced with Tunicamycin (TM). Cells infected with Ad-DHCR24-myc were resistant to TM-induced apoptosis, and showed weaker level of caspase-12 activity. These cells also exhibited lower levels of Bip and CHOP proteins than Ad-LacZ-infected cells. Moreover, a stronger and rapid activation of PERK, and a prolonged activation of JNK and p38 were observed in Ad-LacZ-infected cells. The generation of intracellular reactive oxygen species from ER stress was also diminished by the overexpression of DHCR24. Additionally, intracellular cholesterol level was also elevated in the Ad-DHCR24-infected cells, accompanied by a well-organized formation of caveolae (cholesterol-rich microdomain) on the plasma membrane, and improved colocalization of caveolin-1 and insulin-like growth factor 1 receptor. These results demonstrated for the first time that DHCR24 could protect neuronal cells from apoptosis induced by ER stress.
The School of Life Science, Liaoning University, Shenyang, China.
Xiuli
X
Lu
The School of Life Science, Liaoning University, Shenyang, China.
Yang
Y
Li
The School of Life Science, Liaoning University, Shenyang, China.
Weiqi
W
Wang
The School of Life Science, Liaoning University, Shenyang, China.
Shuchao
S
Chen
The School of Life Science, Liaoning University, Shenyang, China.
Ting
T
Liu
The School of Life Science, Liaoning University, Shenyang, China.
Dan
D
Jia
The School of Life Science, Liaoning University, Shenyang, China.
Xiaoping
X
Quan
The School of Life Science, Liaoning University, Shenyang, China.
Deliang
D
Sun
The School of Life Science, Liaoning University, Shenyang, China.
Alan K
AK
Chang
School of Basic Medical Sciences, Shenyang Medical College, Shenyang, China.
Bing
B
Gao
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D019610:Cytoprotection; D053938:DNA Fragmentation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D015870:Gene Expression; D005822:Genetic Vectors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014415:Tunicamycin / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D051242:Caveolin 1; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C583557:IGF1 protein, human; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D014415:Tunicamycin; D051742:Transcription Factor CHOP; D007334:Insulin-Like Growth Factor I; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D053454:Caspase 12