PERK regulated miR-424(322)-503 cluster fine-tunes activation of IRE1 and ATF6 during Unfolded Protein Response

被引:27
|
作者
Gupta, Ananya [1 ,3 ]
Hossain, Muhammad Mosaraf [1 ,3 ]
Read, Danielle E. [1 ,3 ]
Hetz, Claudio [4 ,5 ,6 ]
Samali, Afshin [2 ]
Gupta, Sanjeev [1 ,3 ]
机构
[1] Natl Univ Ireland Galway, Inst Clin Sci, Sch Med, Discipline Pathol, Galway, Ireland
[2] Natl Univ Ireland Galway, Sch Nat Sci, Apoptosis Res Ctr, Galway, Ireland
[3] Natl Univ Ireland Galway, Lambe Inst Translat Res, Galway, Ireland
[4] Univ Chile, Fac Med, Biomed Neurosci Inst, Santiago, Chile
[5] Univ Chile, Inst Biomed Sci, Ctr Mol Studies Cell, Program Cellular & Mol Biol, Santiago, Chile
[6] FONDAP Ctr Gerosci Brain Hlth & Metab, Santiago, Chile
来源
SCIENTIFIC REPORTS | 2015年 / 5卷
关键词
MESSENGER-RNA; ENDOPLASMIC-RETICULUM; MICRORNA; IRE1-ALPHA; EXPRESSION; GENES; DECAY; XBP1; DEGRADATION; TARGETS;
D O I
10.1038/srep18304
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The endoplasmic reticulum (ER) responds to changes in intracellular homeostasis through activation of the unfolded protein response (UPR). UPR can facilitate the restoration of cellular homeostasis, via the concerted activation of three ER stress sensors, namely IRE1, PERK and ATF6. Global approaches in several cellular contexts have revealed that UPR regulates the expression of many miRNAs that play an important role in the regulation of life and death decisions during UPR. Here we show that expression of miR-424(322)-503 cluster is downregulated during UPR. IRE1 inhibitor (4 mu 8C) and deficiency of XBP1 had no effect on downregulation of miR-424(322)-503 during UPR. Treatment of cells with CCT030312, a selective activator of EIF2AK3/PERK signalling, leads to the downregulation of miR-424(322)-503 expression. The repression of miR-424(322)-503 cluster during conditions of ER stress is compromised in PERK-deficient MEFs. miR-424 regulates the expression of ATF6 via a miR-424 binding site in its 3' UTR and attenuates the ATF6 transcriptional activity during UPR. Further miR-424 had no effect on IRE1-XBP1 axis but enhanced the regulated IRE1-dependent decay (RIDD). Our results suggest that miR-424 constitutes an obligatory fine-tuning mechanism where PERK-mediated downregulation of miR-424(322)-503 cluster regulates optimal activation of IRE1 and ATF6 during conditions of ER stress.
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页数:13
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