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

Gupta, Ananya; Hossain, Muhammad Mosaraf; Read, Danielle E.; Hetz, Claudio; Samali, Afshin; Gupta, Sanjeev

doi:10.1038/srep18304

Cited by 37 publications

(32 citation statements)

References 51 publications

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“…Although the murine ortholog of miR-424, miR-322, is downregulated by activation of the UPR in mouse embryonic fibroblasts (Gupta et al, 2015), miR-424 is not constitutively expressed in the cells used in this study (Chamorro-Jorganes et al, 2011), nor did we detect the miRNA during DENV2 or WNV infection (data not shown). The absence of endogenous miR-424 expression allowed us to use the miR-424 mimic as a tool to identify cellular factors required for viral replication.…”

Section: Discussionmentioning

confidence: 72%

The E3 Ubiquitin Ligase SIAH1 Targets MyD88 for Proteasomal Degradation During Dengue Virus Infection

et al. 2020

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The dengue virus presents a serious threat to human health globally and can cause severe, even life-threatening, illness. Dengue virus (DENV) is endemic on all continents except Antarctica, and it is estimated that more than 100 million people are infected each year. Herein, we further mine the data from a previously described screen for microRNAs (miRNAs) that block flavivirus replication. We use miR-424, a member of the miR-15/16 family, as a tool to further dissect the role of host cell proteins during DENV infection. We observed that miR-424 suppresses expression of the E3 ubiquitin ligase SIAH1, which is normally induced during dengue virus 2 (DENV2) infection through activation of the unfolded protein response (UPR). Specific siRNA-mediated knockdown of SIAH1 also results in inhibition of DENV replication, demonstrating that this target is at least partly responsible for the antiviral activity of miR-424. We further show that SIAH1 binds to and ubiquitinates the innate immune adaptor protein MyD88 and that the antiviral effect of SIAH1 knockdown is reduced in cells in which MyD88 has been deleted by CRISPR/Cas9 gene editing. Additionally, MyD88-dependent signaling, triggered either by DENV2 infection or the Toll-like receptor 7 (TLR7) ligand imiquimod, is increased in cells in which SIAH1 has been knocked down by miR-424 or a SIAH1specific siRNA. These observations suggest an additional pathway by which DENV2 harnesses aspects of the UPR to dampen the host innate immune response and promote viral replication.

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Section: Discussionmentioning

confidence: 72%

The E3 Ubiquitin Ligase SIAH1 Targets MyD88 for Proteasomal Degradation During Dengue Virus Infection

et al. 2020

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“…Under continuous ERS, the UPR can be triggered as a prosurvival process through the transient termination of translation, the induction of a large number of proteins that coordinately function to renature unfolded proteins. However, under conditions of persistent ERS, proapoptotic signals are induced through the activation of several transcription factors, such as CHOP, which is a key downstream regulatory factor of ERS pathway . The data demonstrated that MgIG at 5 mg/mL upregulated the expression of both Calnexin and CHOP in HSCs effectively (Fig.…”

Section: Resultsmentioning

confidence: 89%

Magnesium isoglycyrrhizinate promotes the activated hepatic stellate cells apoptosis via endoplasmic reticulum stress and ameliorates fibrogenesis in vitro and in vivo

et al. 2017

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Varied pathogenetic elements have been touched upon the liver fibrosis, including inflammatory, stress, apoptosis and unfolded proteins aggregation. Magnesium Isoglycyrrhizinate (MgIG) has been accepted to be a neuroprotective effect, hepatoprotective and anti-inflammatory molecule. In our vitro researches, MgIG was considered to activate hepatic stellate cells (HSCs) apoptosis by promoting endoplasmic reticulum stress (ERS) detrimental response to a certain extent. Consequently, MgIG showed its potential therapeutic capacity in fibrogenesis and counteracted the pathogenetic aspects, which were involved in integrating current treatments correcting liver fibrosis. In addition, we further verificated the behavior and pathogenic mechanisms in the CCl -induced liver fibrosis in male mice. What surprised us was that with the treatment of MgIG caused the activation of ERS and resisted the activated HSCs in the protective effects on liver damage. We found MgIG significantly promoted the apoptosis of activated HSCs and protected the CCl -induced liver fibrosis. Main molecules came down to the unfolded protein response signaling pathway. Furthermore, MgIG inhibited the levels of the downstream inflammatory cytokines, which were triggered by CCl -induced liver fibrosis. Here, we reported that MgIG improved behavioral impairments induced by intraperitoneal injection of CCl and decreased the expression of proinflammatory factor, which indicated the preserving effects on liver fibrosis. © 2017 BioFactors, 43(6):836-846, 2017.

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“…MicroRNAs (miRNAs) have emerged recently as key players in UPR signaling in mammalian cells (Maurel and Chevet, 2013), where there is evidence for their involvement in regulating gene expression during ER stress responses (Bartoszewska et al, 2013;Byrd and Brewer, 2013;Gupta et al, 2015). To determine whether they act similarly in maize seedlings, small RNAs were extracted and isolated at the same time points as in the RNAseq analysis.…”

Section: Regulation Of Micrornas During Mid Phasementioning

confidence: 99%

Response to Persistent ER Stress in Plants: A Multiphasic Process That Transitions Cells from Prosurvival Activities to Cell Death

Srivastava

Russo³

et al. 2018

Plant Cell

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The unfolded protein response (UPR) is a highly conserved response that protects plants from adverse environmental conditions. The UPR is elicited by endoplasmic reticulum (ER) stress, in which unfolded and misfolded proteins accumulate within the ER. Here, we induced the UPR in maize () seedlings to characterize the molecular events that occur over time during persistent ER stress. We found that a multiphasic program of gene expression was interwoven among other cellular events, including the induction of autophagy. One of the earliest phases involved the degradation by regulated IRE1-dependent RNA degradation (RIDD) of RNA transcripts derived from a family of peroxidase genes. RIDD resulted from the activation of the promiscuous ribonuclease activity of ZmIRE1 that attacks the mRNAs of secreted proteins. This was followed by an upsurge in expression of the canonical UPR genes indirectly driven by ZmIRE1 due to its splicing of mRNA to make an active transcription factor that directly upregulates many of the UPR genes. At the peak of UPR gene expression, a global wave of RNA processing led to the production of many aberrant UPR gene transcripts, likely tempering the ER stress response. During later stages of ER stress, ZmIRE1's activity declined, as did the expression of survival modulating genes, and , amid a rising tide of cell death. Thus, in response to persistent ER stress, maize seedlings embark on a course of gene expression and cellular events progressing from adaptive responses to cell death.

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

Cited by 37 publications

References 51 publications

The E3 Ubiquitin Ligase SIAH1 Targets MyD88 for Proteasomal Degradation During Dengue Virus Infection

The E3 Ubiquitin Ligase SIAH1 Targets MyD88 for Proteasomal Degradation During Dengue Virus Infection

Magnesium isoglycyrrhizinate promotes the activated hepatic stellate cells apoptosis via endoplasmic reticulum stress and ameliorates fibrogenesis in vitro and in vivo

Response to Persistent ER Stress in Plants: A Multiphasic Process That Transitions Cells from Prosurvival Activities to Cell Death

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