Induction of the Endoplasmic-Reticulum-Stress Response: MicroRNA-34a Targeting of the IRE1α-Branch

Krammes, Lena; Hart, Martin; Rheinheimer, Stefanie; Diener, Caroline; Menegatti, Jennifer; Grässer, Friedrich A.; Keller, Andreas; Meese, Eckart

doi:10.3390/cells9061442

Cited by 15 publications

(8 citation statements)

References 38 publications

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“…Regulation of UPR and ER stress induced apoptosis through silencing the IRE1α mRNA was reported in vivo and in vitro [ 63 ]. The human miRNA, hsa-miR-34a-5p inhibits the tunicamycin induced UPR by targeting and inhibiting the IRE1α protein [ 74 ]. The present study is also in accordance with the above studies that ER-stress induced apoptosis downregulation due to the inhibition of the IRE1α protein.…”

Section: Discussionmentioning

confidence: 99%

Hcmv-miR-UL148D regulates the staurosporine-induced apoptosis by targeting the Endoplasmic Reticulum to Nucleus signaling 1(ERN1)

et al. 2022

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The propensity of viruses to co-opt host cellular machinery by reprogramming the host’s RNA-interference machinery has been a major focus of research, however, regulation of host defense mechanisms by virus-encoded miRNA, is an additional regulatory realm gaining momentum in the arena of host-viral interactions. The Human Cytomegalovirus (HCMV) miRNAs, regulate many cellular pathways alone or in concordance with HCMV proteins, thereby paving a conducive environment for successful infection in the human host. We show that HCMV miRNA, hcmv-miR-UL148D inhibits staurosporine-induced apoptosis in HEK293T cells. We establish that ERN1 mRNA is a bonafide target of hcmv-miR-UL148D and its encoded protein IRE1α is translationally repressed by the overexpression of hcmv-miR-UL148D resulting in the attenuation of apoptosis. Unlike the host microRNA seed sequence (6–8 nucleotides), hcmv-miR-UL148D has long complementarity to 3’ UTR of ERN1 mRNA resulting in mRNA degradation. The repression of IRE1α by the hcmv-miR-UL148D further downregulates Xbp1 splicing and c-Jun N-terminal kinase phosphorylation thus regulating ER-stress and ER-stress induced apoptotic pathways. Strikingly, depletion of ERN1 attenuates staurosporine-induced apoptosis which further suggests that hcmv-miR-UL148D functions through regulation of its target ERN1. These results uncover a role for hcmv-miR-UL148D and its target ERN1 in regulating ER stress-induced apoptosis.

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Section: Discussionmentioning

confidence: 99%

Hcmv-miR-UL148D regulates the staurosporine-induced apoptosis by targeting the Endoplasmic Reticulum to Nucleus signaling 1(ERN1)

et al. 2022

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“…Together, these findings might point to a positive feedback loop of IRE1 and miR-34a-5p (Krammes et al, 2020). In a mice model of AD, ER stress-induced miR-200c to reduce the expression of PTEN in the PI3K/Akt signaling pathway at the initial stage of the disease.…”

Section: The Interplay Between Ncrnas and Inflammation In Neurodegene...mentioning

confidence: 91%

“…On the other hand, it was also reported that IRE1 could conversely regulate miR‐34a expression through its sustained RNase activity. Together, these findings might point to a positive feedback loop of IRE1 and miR‐34a‐5p (Krammes et al, 2020). In a mice model of AD, ER stress‐induced miR‐200c to reduce the expression of PTEN in the PI3K/Akt signaling pathway at the initial stage of the disease.…”

Section: The Interplay Between Ncrnas and Inflammation In Neurodegene...mentioning

confidence: 97%

The emerging role of noncoding RNAs in neuroinflammation: Implications in pathogenesis and therapeutic approaches

Ebrahimi

Golestani

2021

Journal Cellular Physiology

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Noncoding RNAs (ncRNAs) are important regulators of gene expression in different cell processes. Due to their ability in monitoring neural development genes, these transcripts confer neurons with the potential to exert broad control over the expression of genes for performing neurobiological functions.Although the change of ncRNA expression in different neurodegenerative diseases has been reviewed elsewhere, only recent evidence drove our attention to unravel the involvement of these molecules in neuroinflammation within these devastating disorders. Remarkably, the interactions between ncRNAs and inflammatory pathways are not fully recognized. Therefore, this review has focused on the interplay between diverse inflammatory pathways and the related ncRNAs, including microRNAs, long noncoding RNAs, and competing endogenous RNAs in Alzheimer's disease, Parkinson's diseases, amyotrophic lateral sclerosis, epilepsy, multiple sclerosis, Huntington's disease, and prion diseases. Providing novel insights in the field of combining biomarkers is a critical step for using them as diagnostic tools and therapeutic targets in clinical settings.

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“…miRNAs help in modulation of the cellular stress response, by regulating UPR key component levels. Krammes et al, 2020 reported that miR-34a-5p plays a vital role in the regulation of the IRE1α branch. Its overexpression targets BIP , IRE1 α, and XBP1 genes and subsequently leads to a reduction in IRE1α and XBP1s thereby modulating UPR signaling.…”

Section: Connection Between Er Upr Signaling Pathw...mentioning

confidence: 99%

Deciphering the Link Between ERUPR Signaling and MicroRNA in Pathogenesis of Alzheimer’s Disease

Yasmeen

Datta

Kumar

et al. 2022

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a neurodegenerative proteinopathic disease. The deposits of misfolded Amyloid β and Tau proteins in the brain of patients with AD suggest an imbalance in endoplasmic reticulum (ER) proteostasis. ER stress is due to accumulation of aberrant proteins in the ER lumen, which then leads to activation of three sensor protein pathways that ultimately evokes the adaptive mechanism of the unfolded protein response (UPR). The UPR mechanism operates via adaptive UPR and the apoptotic UPR. Adaptive UPR tries to restore imbalance in ER hemostasis by decreasing protein production, enhanced chaperone involvement to restore protein folding, misfolded protein decay by proteasome, and suppression of ribosomal translation ultimately relieving the excessive protein load in the ER. Subsequently, apoptotic UPR activated under severe ER stress conditions triggers cell death. MicroRNAs (miRNAs) are small non-coding protein causing dysregulated translational of mRNAs in a sequential manner. They are considered to be critical elements in the maintenance of numerous cellular activities, hemostasis, and developmental processes. Therefore, upregulation or downregulation of miRNA expression is implicated in several pathogenic processes. Evidence from scientific studies suggest a strong correlation between ERUPR signaling and miRNA dysregulation but the research done is still dormant. In this review, we summarized the cross-talk between ER stress, and the UPR signaling processes and their role in AD pathology by scrutinizing and collecting information from original research and review articles.

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Induction of the Endoplasmic-Reticulum-Stress Response: MicroRNA-34a Targeting of the IRE1α-Branch

Cited by 15 publications

References 38 publications

Hcmv-miR-UL148D regulates the staurosporine-induced apoptosis by targeting the Endoplasmic Reticulum to Nucleus signaling 1(ERN1)

Hcmv-miR-UL148D regulates the staurosporine-induced apoptosis by targeting the Endoplasmic Reticulum to Nucleus signaling 1(ERN1)

The emerging role of noncoding RNAs in neuroinflammation: Implications in pathogenesis and therapeutic approaches

Deciphering the Link Between ERUPR Signaling and MicroRNA in Pathogenesis of Alzheimer’s Disease

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