Recent advances in signal integration mechanisms in the unfolded protein response

Karagöz, G. Elif; Aragón, Tomás; Acosta‐Alvear, Diego

doi:10.12688/f1000research.19848.1

Cited by 25 publications

(20 citation statements)

References 150 publications

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“…This behavior suggests that affected cells in the same tissue exhibit a range of (successful and unsuccessful) attempts in adaptive response to chronic ER stress. Such a finding is consistent with the broader notion that a myriad of prosurvival and prodeath signals are generated as downstream consequences of ER stress ( 5 ), and there are likely to be both complex (and possibly subtle) changes in the profile and balance of these activities that trigger death in some cells while allowing survival and even proliferation of adjacent cells of the same cell type.…”

Section: Introductionsupporting

confidence: 86%

Cell death–associated lipid droplet protein CIDE-A is a noncanonical marker of endoplasmic reticulum stress

Morishita¹,

Kellogg²,

Larkin³

et al. 2021

JCI Insight

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Secretory protein misfolding has been linked to ER stress and cell death. We expressed a TG rdw transgene encoding TG-G(2298)R, a misfolded mutant thyroglobulin reported to be linked to thyroid cell death. When the TG rdw transgene was expressed at low-level in thyrocytes of TG cog/cog mice that experience severe ER stress, we observed increased thyrocyte cell death and increased expression of CIDE-A (Cell death-inducing DFFA-like effector-A, a protein of lipid droplets) in whole thyroid gland. Here we demonstrate that acute ER stress in cultured PCCL3 thyrocytes increases Cidea mRNA levels, maintained at least in part by increased mRNA stability, while being negatively regulated by ATF6with similar observations other cell types. CIDE-A protein is sensitive to proteasomal degradation yet is stabilized by ER stress, and elevated expression levels accompany increased cell death. Unlike acute ER stress, PCCL3 cells adapted and surviving chronic ER stress maintain a disproportionately lower relative mRNA level of Cidea compared to that of other, classical ER stress markers, as well as a blunted Cidea mRNA response to a new, unrelated acute ER stress challenge. We suggest that CIDE-A is a novel marker linked to a non-canonical ER stress-response program, with implications for cell death and survival.

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Section: Introductionsupporting

confidence: 86%

Cell death–associated lipid droplet protein CIDE-A is a noncanonical marker of endoplasmic reticulum stress

Morishita¹,

Kellogg²,

Larkin³

et al. 2021

JCI Insight

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“…However, under prolonged ER stress, UPR can also induce apoptotic cell death if homeostasis cannot be re-established and accumulation of misfolded protein becomes toxic. Apoptosis is triggered potentially via UPR-mediated and Ca 2+ -mediated caspase activation pathways and recruitment of mitochondria ( Kim et al, 2006 ; Fung and Liu, 2014 ; Karagöz et al, 2019 ). Indeed, Ca 2+ homeostasis plays a major role in ER stress and UPR-mediated apoptosis induction.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?

Vela

2020

Front. Pharmacol.

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Outbreaks of emerging infections, such as COVID-19 pandemic especially, confront health professionals with the unique challenge of treating patients. With no time to discover new drugs, repurposing of approved drugs or in clinical development is likely the only solution. Replication of coronaviruses (CoVs) occurs in a modified membranous compartment derived from the endoplasmic reticulum (ER), causes host cell ER stress and activates pathways to facilitate adaptation of the host cell machinery to viral needs. Accordingly, modulation of ER remodeling and ER stress response might be pivotal in elucidating CoV-host interactions and provide a rationale for new therapeutic, host-based antiviral approaches. The sigma-1 receptor (Sig-1R) is a ligand-operated, ER membrane-bound chaperone that acts as an upstream modulator of ER stress and thus a candidate host protein for host-based repurposing approaches to treat COVID-19 patients. Sig-1R ligands are frequently identified in in vitro drug repurposing screens aiming to identify antiviral compounds against CoVs, including severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Sig-1R regulates key mechanisms of the adaptive host cell stress response and takes part in early steps of viral replication. It is enriched in lipid rafts and detergent-resistant ER membranes, where it colocalizes with viral replicase proteins. Indeed, the non-structural SARS-CoV-2 protein Nsp6 interacts with Sig-1R. The activity of Sig-1R ligands against COVID-19 remains to be specifically assessed in clinical trials. This review provides a rationale for targeting Sig-1R as a host-based drug repurposing approach to treat COVID-19 patients. Evidence gained using Sig-1R ligands in unbiased in vitro antiviral drug screens and the potential mechanisms underlying the modulatory effect of Sig-1R on the host cell response are discussed. Targeting Sig-1R is not expected to reduce dramatically established viral replication, but it might interfere with early steps of virus-induced host cell reprogramming, aid to slow down the course of infection, prevent the aggravation of the disease and/or allow a time window to mature a protective immune response. Sig-1R-based medicines could provide benefit not only as early intervention, preventive but also as adjuvant therapy.

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“…Endoplasmic reticulum stress (ERS) can be caused by an imbalance of Ca 2+ , excess reactive oxygen species, the accumulation of misfolded proteins, and many other perturbations that disrupt cell homeostasis [16][17][18] . There are three ERresident proximal sensors of unfolded proteins and ERS: ATF6, IRE1, and PERK 19,20 . Normally, GRP78 can bind these three molecules at the inner end of the ER to maintain their resting state.…”

Section: Introductionmentioning

confidence: 99%

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade

Hao

et al. 2020

Cell Death Dis

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Multiple vaginal delivery (MVD) is an important factor for pelvic floor muscle (PFM) function decline and pelvic floor dysfunction (PFD). PFD is common in middle-aged and elderly women, but its pathogenesis is not clear. In this study, we found that the expression of CACNA1H was lower in the PFM of old mice after MVD compared with old or adult mice. In in-vitro studies, we found that treatment with the T-type Ca 2+ channel (T-channel) inhibitor NNC-55 or downregulation of the CACNA1H gene by siRNA intervention promoted myotube atrophy and apoptosis. Mechanistically, we revealed that NNC-55 increased the expression of GRP78 and DDIT3 in myotubes, indicating endoplasmic reticulum stress (ERS) activation, and that the IRE1 and PERK pathways might be involved in this effect. NNC-55 induced the formation of autophagosomes but inhibited autophagy flux. Moreover, rapamycin, an autophagy activator, did not rescue myotube atrophy or apoptosis induced by NNC-55, and the autophagy inhibitors 3-MA and HCQ accelerated this damage. Further studies showed that the ERS inhibitors 4-PBA and TUDAC relieved NNC-55-induced damage and autophagy flux blockade. Finally, we found multisite muscle atrophy and decreased muscle function in Cacna1h −/− (TH-null) mice, as well as increased autophagy inhibition and apoptotic signals in the PFM of old WT mice after MVD and TH-null mice. Taken together, our results suggest that MVD-associated PFD is partially attributed to CACNA1H downregulation-induced PFM atrophy and that ERS is a potential therapeutic target for this disease.

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Recent advances in signal integration mechanisms in the unfolded protein response

Cited by 25 publications

References 150 publications

Cell death–associated lipid droplet protein CIDE-A is a noncanonical marker of endoplasmic reticulum stress

Cell death–associated lipid droplet protein CIDE-A is a noncanonical marker of endoplasmic reticulum stress

Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?

CACNA1H downregulation induces skeletal muscle atrophy involving endoplasmic reticulum stress activation and autophagy flux blockade

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