PERK Regulated MiR-424(322)-503 Cluster Fine-tunes Activation of IRE1 and ATF6 During Unfolded Protein Response

Overview

Journal Sci Rep

Specialty Science

Date 2015 Dec 18

PMID 26674075

Citations 25

Authors

Ananya Gupta

Muhammad Mosaraf Hossain

Danielle E Read

Claudio Hetz

Afshin Samali

Sanjeev Gupta

Affiliations

Soon will be listed here.

Abstract

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 μ8C) 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.

Citing Articles

The Involvement of the microRNAs miR-466c and miR-340 in the Palmitate-Mediated Dysregulation of Gonadotropin-Releasing Hormone Gene Expression.

Nkechika V, Zhang N, Belsham D Genes (Basel). 2024; 15(4).

PMID: 38674332 PMC: 11048885. DOI: 10.3390/genes15040397.

Decoding contextual crosstalk: revealing distinct interactions between non-coding RNAs and unfolded protein response in breast cancer.

Karamali N, Daraei A, Rostamlou A, Mahdavi R, Jonoush Z, Ghadiri N Cancer Cell Int. 2024; 24(1):104.

PMID: 38468244 PMC: 10926595. DOI: 10.1186/s12935-024-03296-3.

UPR-Induced miR-616 Inhibits Human Breast Cancer Cell Growth and Migration by Targeting c-MYC.

Arabkari V, Sultana A, Barua D, Webber M, Smith T, Gupta A Int J Mol Sci. 2023; 24(17).

PMID: 37685841 PMC: 10487498. DOI: 10.3390/ijms241713034.

MicroRNA-322 overexpression reduces neural tube defects in diabetic pregnancies.

Wang G, Song S, Shen W, Reece E, Yang P Am J Obstet Gynecol. 2023; 230(2):254.e1-254.e13.

PMID: 37531989 PMC: 10828117. DOI: 10.1016/j.ajog.2023.07.048.

TGFβ1 regulates HRas-mediated activation of IRE1α through the PERK-RPAP2 axis in keratinocytes.

Mogre S, Blazanin N, Walsh H, Ibinson J, Minnich C, Hu C Mol Carcinog. 2022; 61(10):958-971.

PMID: 35975910 PMC: 9486931. DOI: 10.1002/mc.23453.

References

Cawley K, Logue S, Gorman A, Zeng Q, Patterson J, Gupta S . Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion. PLoS One. 2013; 8(8):e73870. PMC: 3747093. DOI: 10.1371/journal.pone.0073870. View

Gupta A, Read D, Gupta S . Assays for induction of the unfolded protein response and selective activation of the three major pathways. Methods Mol Biol. 2015; 1292:19-38. DOI: 10.1007/978-1-4939-2522-3_2. View

Lisbona F, Rojas-Rivera D, Thielen P, Zamorano S, Todd D, Martinon F . BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alpha. Mol Cell. 2009; 33(6):679-91. PMC: 2818874. DOI: 10.1016/j.molcel.2009.02.017. View

Malhotra J, Kaufman R . The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol. 2007; 18(6):716-31. PMC: 2706143. DOI: 10.1016/j.semcdb.2007.09.003. View

Lee A, Heidtman K, Hotamisligil G, Glimcher L . Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion. Proc Natl Acad Sci U S A. 2011; 108(21):8885-90. PMC: 3102350. DOI: 10.1073/pnas.1105564108. View

Bartoszewski R, Brewer J, Rab A, Crossman D, Bartoszewska S, Kapoor N . The unfolded protein response (UPR)-activated transcription factor X-box-binding protein 1 (XBP1) induces microRNA-346 expression that targets the human antigen peptide transporter 1 (TAP1) mRNA and governs immune regulatory genes. J Biol Chem. 2011; 286(48):41862-41870. PMC: 3308892. DOI: 10.1074/jbc.M111.304956. View

Duan Q, Wang X, Gong W, Ni L, Chen C, He X . ER stress negatively modulates the expression of the miR-199a/214 cluster to regulates tumor survival and progression in human hepatocellular cancer. PLoS One. 2012; 7(2):e31518. PMC: 3281082. DOI: 10.1371/journal.pone.0031518. View

Babar I, Slack F, Weidhaas J . miRNA modulation of the cellular stress response. Future Oncol. 2008; 4(2):289-98. DOI: 10.2217/14796694.4.2.289. View

Byrd A, Aragon I, Brewer J . MicroRNA-30c-2* limits expression of proadaptive factor XBP1 in the unfolded protein response. J Cell Biol. 2012; 196(6):689-98. PMC: 3308703. DOI: 10.1083/jcb.201201077. View

10.

Samali A, Fitzgerald U, Deegan S, Gupta S . Methods for monitoring endoplasmic reticulum stress and the unfolded protein response. Int J Cell Biol. 2010; 2010:830307. PMC: 2821749. DOI: 10.1155/2010/830307. View

11.

Gregory R, Chendrimada T, Cooch N, Shiekhattar R . Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell. 2005; 123(4):631-40. DOI: 10.1016/j.cell.2005.10.022. View

12.

Hollien J, Lin J, Li H, Stevens N, Walter P, Weissman J . Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol. 2009; 186(3):323-31. PMC: 2728407. DOI: 10.1083/jcb.200903014. View

13.

Stockwell S, Platt G, Barrie S, Zoumpoulidou G, Te Poele R, Aherne G . Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. PLoS One. 2012; 7(1):e28568. PMC: 3257223. DOI: 10.1371/journal.pone.0028568. View

14.

Bushati N, Cohen S . microRNA functions. Annu Rev Cell Dev Biol. 2007; 23:175-205. DOI: 10.1146/annurev.cellbio.23.090506.123406. View

15.

Eletto D, Eletto D, Boyle S, Argon Y . PDIA6 regulates insulin secretion by selectively inhibiting the RIDD activity of IRE1. FASEB J. 2015; 30(2):653-65. PMC: 4714551. DOI: 10.1096/fj.15-275883. View

16.

Oikawa D, Tokuda M, Iwawaki T . Site-specific cleavage of CD59 mRNA by endoplasmic reticulum-localized ribonuclease, IRE1. Biochem Biophys Res Commun. 2007; 360(1):122-7. DOI: 10.1016/j.bbrc.2007.06.020. View

17.

Rodriguez D, Zamorano S, Lisbona F, Rojas-Rivera D, Urra H, Cubillos-Ruiz J . BH3-only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1α. EMBO J. 2012; 31(10):2322-35. PMC: 3364744. DOI: 10.1038/emboj.2012.84. View

18.

Gupta S, Deepti A, Deegan S, Lisbona F, Hetz C, Samali A . HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction. PLoS Biol. 2010; 8(7):e1000410. PMC: 2897763. DOI: 10.1371/journal.pbio.1000410. View

19.

Gupta S, Read D, Deepti A, Cawley K, Gupta A, Oommen D . Perk-dependent repression of miR-106b-25 cluster is required for ER stress-induced apoptosis. Cell Death Dis. 2012; 3:e333. PMC: 3388242. DOI: 10.1038/cddis.2012.74. View

20.

Cross B, Bond P, Sadowski P, Jha B, Zak J, Goodman J . The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc Natl Acad Sci U S A. 2012; 109(15):E869-78. PMC: 3326519. DOI: 10.1073/pnas.1115623109. View