Sepsis is a systemic inflammatory state in response to infection, and concomitant acute kidney injury (AKI) increases mortality significantly. Endoplasmic reticulum stress is activated in many cell ...types upon microbial infection and modulates inflammation. The role of endoplasmic reticulum signaling in the kidney during septic AKI is unknown. Here we tested the role of the spliced X-box binding protein 1 (Xbp1s), a key component of the endoplasmic reticulum stress-activated pathways, in the renal response to sepsis in the lipopolysaccharide (LPS) model. Xbp1s was increased in the kidneys of mice treated with LPS but not in other models of AKI, or several chronic kidney disease models. The functional significance of Xbp1s induction was examined by genetic manipulation in renal tubules. Renal tubule-specific overexpression of Xbp1s caused severe tubule dilation and vacuolation with expression of the injury markers Kim1 and Ngal, the pro-inflammatory molecules interleukin-6 (Il6) and Toll-like receptor 4 (Tlr4), decreased kidney function and 50% mortality in five days. Renal tubule-specific genetic ablation of Xbp1 had no phenotype at baseline. However, after LPS, Xbp1 knockdown mice displayed lower renal NGAL, pro-apoptotic factor CHOP, serum creatinine levels, and a tendency towards lower Tlr4 compared to LPS-treated mice with intact Xbp1s. LPS treatment in Xbp1s-overexpressing mice caused a mild increase in NGAL and CHOP compared to LPS-treated mice without genetic Xbp1s overexpression. Thus, increased Xbp1s signaling in renal tubules is unique to sepsis-induced AKI and contributes to renal inflammation and injury. Inhibition of this pathway may be a potential portal to alleviate injury.
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Programmed cell death (PCD) induced by endoplasmic reticulum (ER) stress is implicated in variousplant physiological processes, yet its mechanism is still elusive. An activation of caspase-3-like ...enzymatic activity was clearly demonstrated but the role of the two known plant proteases with caspase-3-like activity, cathepsin B and proteasome subunit PBA1, remains to be established.
Both genetic downregulation and chemical inhibition were used to investigate the function of cathepsin B and PBA1 in ER-stress-induced PCD (ERSID). Transcript level and activity labelling of cathepsin B were used to assess activation. To study tonoplast rupture, a plant PCD feature, both confocal and electronic microscopies were used.
Cathepsin B downregulation reduced reactive oxygen species (ROS) accumulation and ERSID without affecting the induction of the unfolded protein response (UPR), but downregulation of PBA1 increased UPR and ERSID. Tonoplast rupture was not altered in the cathepsin B mutant and cathepsin B activation was independent of vacuolar processing enzyme (VPE). VPE activity was independent of cathepsin B.
ERSID is regulated positively by cathepsin B and negatively by PBA1, revealing a complex picture behind caspase-3-like activity in plants. Cathepsin B may execute its function after tonoplast rupture and works in parallel with VPE.
Glutamatergic dysregulation has served as one common pathophysiology of major depressive disorder (MDD) and a promising target for treatment intervention. Previous studies implicate neurotransmission ...via metabotropic glutamate receptors (mGluRs) and Homer1 in stress-induced anhedonia, but the mechanisms have not been well elucidated. In the present study, we used two different animal models of depression, chronic social defeat stress (CSDS) and chronic restraint stress (CRS), to investigate the expression of Homer1 isoforms and functional interaction with mGluRs. We found that chronic stress selectively upregulated the expression of Homer1b/c in the hippocampus, whereas the level of Homer1a was unchanged. Additionally, there was a significant negative correlation between the levels of Homer1-mGluR5 signaling and depressive-like behaviors. Both application of paired-pulse low-frequency stimulation (PP-LFS) and the selective group 1 mGluRs agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) significantly enhanced mGluR-dependent long-term depression (LTD) at CA3-CA1 pyramidal cell synapses in slices from susceptible mice, whereas there was no change in NMDAR-dependent LTD induced by LFS. Furthermore, these effects were associated with the internalization of surface AMPARs in hippocampal pyramidal neurons, including reduced the expression of AMPARs and amplitude of AMPARs-mediated mEPSC. Finally, we found that chronic stress activated the KR-like ER kinase-eukaryotic initiation factor 2α (PERK-eIF2α) signaling pathway, subsequently phosphorylated cAMP response element binding protein (CREB) at the S129 and reduced the BDNF level, eventually leading to the impairment of synaptic transmission and depressive-like behaviors. Therefore, our study suggests that PERK-eIF2α acts as a critical target downstream of Homer1-mGluR5 complex to mediate chronic stress-induced depressive-like behaviors, and highlights them as a potential target for the treatment of mood disorder.
•Chronic stress increases Homer1-mGluR5 levels in the hippocampus of mice.•CSDS enhances hippocampal mGluR-dependent long-term depression (mGluR-LTD) via the internalization of surface AMPARs.•PKR-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) phosphorylation facilitates mGluR-LTD induced by CSDS.
Endoplasmic reticulum (ER) stress, a common cellular stress response induced by various factors that interfere with cellular homeostasis, may trigger cell apoptosis. Autophagy is an important and ...conserved mechanism for eliminating aggregated proteins and maintaining protein stability of cells, which is closely associated with ER stress and ER stress–induced apoptosis. In this paper, we report for the first time that Hhatl, an ER-resident protein, is downregulated in response to ER stress. Hhatl overexpression alleviated ER stress and ER stress induced apoptosis in cells treated with tunicamycin or thapsigargin, whereas Hhatl knockdown exacerbated ER stress and apoptosis. Further study showed that Hhatl attenuates ER stress by promoting autophagic flux. Mechanistically, we found that Hhatl promotes autophagy by associating with autophagic protein LC3 (microtubule-associated protein 1A/1B-light chain 3) via the conserved LC3-interacting region motif. Noticeably, the LC3-interacting region motif was essential for Hhatl-regulated promotion of autophagy and reduction of ER stress. These findings demonstrate that Hhatl ameliorates ER stress via autophagy activation by interacting with LC3, thereby alleviating cellular pressure. The study indicates that pharmacological or genetic regulation of Hhatl-autophagy signaling might be potential for mediating ER stress and related diseases.
Recent work provides evidence for the new terminology, ‘endoplasmic reticulum (ER) stress response or sensing failure’, in relation to metabolic disease. We seek to identify and amass possible ...conditions of ER stress response failure in various metabolic and age-related pathogenesis, including obesity and diabetes.
VPS34-IN1 induces apoptosis of ER+ breast cancer cells via activating PERK/ATF4/CHOP pathway.
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VPS34-IN1 is a specific selective inhibitor of Class III Phosphatidylinositol 3-kinase ...(PI3K) and has been shown to exhibit a significant antitumor effect in leukemia and liver cancer. In current study, we focused on the anticancer effect and potential mechanism of VPS34-IN1 in estrogen receptor positive (ER+ ) breast cancer. Our results revealed that VPS34-IN1 inhibited the viability of ER+ breast cancer cells in vitro and in vivo. Flow cytometry and western blot analyses showed that VPS34-IN1 treatment induced breast cancer cell apopotosis. Interestingly, VPS34-IN1 treatment activated protein kinase R (PKR)-like ER kinase (PERK) branch of endoplasmic reticulum (ER) stress. Furthermore, knockdown of PERK by siRNA or inhibition of PERK activity by chemical inhibitor GSK2656157 could attenuate VPS34-IN1-mediated apoptosis in ER+ breast cancer cells. Collectively, VPS34-IN1 has an antitumor effect in breast cancer, and it may result from activating PERK/ATF4/CHOP pathway of ER stress to induce cell apoptosis. These findings broaden our understanding of the anti-breast cancer effects and mechanisms of VPS34-IN1 and provide new ideas and reference directions for the treatment of ER+ breast cancer.
Endoplasmic reticulum (ER) stress, a common cellular stress response, is closely related to the activation of autophagy that is an important and evolutionarily conserved mechanism for maintaining ...cellular homeostasis. Autophagy induced by ER stress mainly includes the ER stress‐mediated autophagy and ER‐phagy. The ER stress‐mediated autophagy is characterized by the generation of autophagosomes that include worn‐out proteins, protein aggregates, and damaged organelles. While the autophagosomes of ER‐phagy selectively include ER membranes, and the double membranes also derive, at least in part, from the ER. The signaling pathways of IRE1α, PERK, ATF6, and Ca2+ are necessary for the activation of ER stress‐mediated autophagy, while the receptor‐mediated selective ER‐phagy degrades the ER is Atg40/FAM134B. The ER stress‐mediated autophagy and ER‐phagy not only have differences, but also have connections. The activation of ER‐phagy requires the core autophagy machinery, and the ER‐phagy may be a branch of ER stress‐mediated autophagy that selectively targets the ER. However, the determined factors that control the changeover switch between ER stress‐mediated autophagy and ER‐phagy are largely obscure, which may be associated with the type of cells and the extent of stimulation. This review summarized the crosstalk between ER stress‐mediated autophagy and ER‐phagy and their signaling networks. Additionally, we discussed the possible factors that influence the type of autophagy induced by ER stress.
Under ER stress condition, the ER stress‐mediated autophagy and ER‐phagy can be activated, and both involved in UPR and the core autophagy machinery. However, the determined factors that control the changeover switch between ER stress‐mediated autophagy and ER‐phagy, are unclear. And we speculate that the type of cells and the extent of stimulation may be associated with the type of autophagy induced by ER stress.
Unfolded Protein Response in Arabidopsis Ruberti, Cristina; Brandizzi, Federica
Methods in molecular biology (Clifton, N.J.),
2024, Volume:
2772
Journal Article
Open access
The unfolded protein response (UPR) is a highly regulated signaling pathway that is largely conserved across eukaryotes. It is essential for cell homeostasis under environmental and physiological ...conditions that perturb the protein folding in the endoplasmic reticulum (ER). Arabidopsis is one of the outstanding multicellular model systems in which to investigate the UPR. Here, we described a protocol to induce the UPR in plants, specifically Arabidopsis, and to estimate their ability to cope with ER stress through the quantification of physiological parameters.
An accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) leads to stress conditions. To mitigate such circumstances, stressed cells activate a homeostatic intracellular ...signaling network cumulatively called the unfolded protein response (UPR), which orchestrates the recuperation of ER function. Macroautophagy (hereafter autophagy), an intracellular lysosome-mediated bulk degradation pathway for recycling and eliminating wornout proteins, protein aggregates, and damaged organelles, has also emerged as an essential protective mechanism during ER stress. These 2 systems are dynamically interconnected, and recent investigations have revealed that ER stress can either stimulate or inhibit autophagy. However, the stress-associated molecular cues that control the changeover switch between induction and inhibition of autophagy are largely obscure. This review summarizes the crosstalk between ER stress and autophagy and their signaling networks mainly in mammalian-based systems. Additionally, we highlight current knowledge on selective autophagy and its connection to ER stress.
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