Endoplasmic Reticulum Stress-induced Autophagy Research Articles

A Marine-Derived Small Molecule Inhibits Prostate Cancer Growth by Promoting Endoplasmic Reticulum Stress Induced Apoptosis and Autophagy.

MHO7 (6-epi-ophiobolin G), a novel component extracted from a mangrove fungus, exhibits significant anticancer effects against breast cancer. However, the precise mechanism underlying the anticancer effects of MHO7 in prostate cancer (PCa) is yet to be fully elucidated. Therefore, this study was undertaken to assess the effect of MHO7 on PCa cells and elucidate its underlying mechanism. A series of in vitro experiments were conducted, including Cell Counting Kit-8, and plate clone formation assays, flow cytometry analysis, electron microscopy, immunofluorescence staining, western blotting, and molecular dynamics simulation. Additionally, in vivo tumor xenograft models were employed. Our findings revealed that MHO7 could induce cellular autophagy at low concentration (2 μM) and apoptosis at relatively high concentration (4 and 8 μM), leading to significant PCa cell growth inhibition. Furthermore, MHO7 triggered endoplasmic reticulum (ER) stress, which subsequently stimulated autophagy and apoptosis via IRE1α/XBP-1s signaling pathway activation. Notably, IRE1α knockdown markedly reduced MHO7-induced autophagy and apoptosis. Moreover, MHO7 targeted the IRE1α protein, thereby enhancing its stability. MHO7 also exhibited substantial anticancer activity in tumor xenograft models. Our study revealed that MHO7 holds considerable potential as an anticancer agent against PCa, attributable to its activation of ER stress-induced autophagy and apoptosis at different concentrations, facilitated by the upregulation of IRE1α expression.

Juan-tong-yin potentially impacts endometriosis pathophysiology by enhancing autophagy of endometrial stromal cells via unfolded protein reaction-triggered endoplasmic reticulum stress

Ethnopharmacological relevanceEndometriosis (EMs) is characterized by inflammatory lesions, dysmenorrhea, infertility, and chronic pelvic pain. Single-target medications often fail to provide systemic therapeutic results owing to the complex mechanism underlying endometriosis. Although traditional Chinese medicines—such as Juan-Tong-Yin (JTY)—have shown promising results, their mechanisms of action remain largely unknown. Aim of the studyTo elucidate the therapeutic mechanism of JTY in EMs, focusing on endoplasmic reticulum (ER) stress-induced autophagy. Materials and methodsThe major components of JTY were detected using high-performance liquid chromatography–mass spectrometry (HPLC–MS). The potential mechanism of JTY in EMs treatment was predicted using network pharmacological analysis. Finally, the pathogenesis of EMs was validated in a clinical case-control study and the molecular mechanism of JTY was validated in vitro using endometrial stromal cells (ESCs). ResultsIn total, 241 compounds were analyzed and identified from JTY using UPLC–MS. Network pharmacology revealed 288 targets between the JTY components and EMs. Results of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses indicated that regulating autophagy, migration, apoptosis, and inflammation were the key mechanisms of JTY in treating EMs. Meanwhile, we found that protein kinase R-like endoplasmic reticulum kinase (PERK), Beclin-1, and microtubule-associated protein light chain 3 B (LC3B) expressions were lower in endometria of patients with EMs than in those with normal eutopic endometria (p < 0.05). Additionally, during in vitro experiments, treatment with 20% JTY-containing serum significantly suppressed ESC proliferation, achieving optimal effects after 48 h. Electron microscopy revealed significantly increased autophagy flux in the JTY group compared with the control group. Moreover, JTY treatment significantly reduced the migratory and invasive abilities of ESCs and upregulated protein expression of PERK, eukaryotic initiation factor 2α (eIF2α)/phospho-eukaryotic initiation factor 2α (p-eIF2α), activating Transcription Factor-4 (ATF4), Beclin-1, and LC3BII/I, while subsequently downregulating NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and interleukin 18 (IL-18) expression. However, administration of GSK2656157—a highly selective PERK inhibitor—reversed these changes. ConclusionJTY ameliorates EMs by activating PERK associated with unfolded protein reaction, enhancing cell ER stress and autophagy, improving the inflammatory microenvironment, and decreasing the migration and invasion of ESCs.

Stub1 ameliorates ER stress-induced neural cell apoptosis and promotes locomotor recovery through restoring autophagy flux after spinal cord injury

Endoplasmic reticulum (ER) stress-induced apoptosis and autophagy flux blockade significantly contribute to neuronal pathology of spinal cord injury (SCI). Yet, the molecular interplay between these two distinctive pathways in mediating the pathology of SCI remains largely unexplored. Currently, we aimed at exploring the crucial role of Stub1 in maintaining ER homeostasis and regulating autophagic flux after SCI. Our results demonstrate that Stub1 reduces ER stress induced neuronal apoptosis, promotes axonal regeneration, inhibits glial scar formation and fosters functional recovery by restoring autophagic flux following SCI. Stub1 enhances autophagic flux following SCI by alleviating the permeabilization of lysosomal membrane through activating TFEB. Importantly, we showed that Stub1 promotes the activation of TFEB by targeting HDAC2 for ubiquitination and degradation. Furthermore, the neuroprotective effect of Stub1 on SCI was abrogated by chloroquine administration, underscoring the essential role of Stub1-mediated enhancement of autophagic flux in its protective effects against SCI. Collectively, our data highlights the vital role of Stub1 in regulating ER stress and autophagy flux after SCI, and propose its potential as a promising target for neuroprotective interventions in SCI.

SARS-CoV-2 nonstructural protein 6 triggers endoplasmic reticulum stress-induced autophagy to degrade STING1

ABSTRACT SARS-CoV-2 poses a substantial global threat owing to the emergence of several highly transmissible variants. Autophagy is an intracellular degradation process that maintains cellular homeostasis and combats the invading pathogens. SARS-CoV-2 can trigger autophagy and antagonize interferon production. However, the underlying mechanisms remain elusive, particularly for different variants. Here, we found that SARS-CoV-2 nonstructural protein (NSP) 6 inhibited interferon production by promoting macroautophagy/autophagy-mediated STING1 degradation. Mechanistically, NSP6 induced endoplasmic reticulum stress and bound to HSPA5/GRP78, leading to the activation of EIF2AK3/PERK-EIF2A/EIf2α pathway-mediated autophagy, which was associated with lysosomal degradation of STING1 and downregulation of interferon production. Moreover, the 81–120 amino acid (aa) region of NSP6 is critical for autophagy induction and STING1 degradation. Interestingly, NSP6 harboring a three aa deletion in the 81–120 aa region of some SARS-CoV-2 variants led to reduced autophagy, STING1 degradation, and increased host antiviral immunity. Collectively, this study demonstrated a major function of NSP6 in the SARS-CoV-2 evasion of host antiviral immunity by triggering endoplasmic reticulum stress-induced autophagy to degrade STING1 and that enhancement of host antiviral immunity induced by NSP6 variants with a three-aa deletion might be responsible for the attenuation of SARS-CoV-2 variants. Abbreviations aa: amino acid; ATF6: activating transcription factor 6; ATG5: autophagy related 5; CCPG1: cell cycle progression 1; CFTR: CF transmembrane conductance regulator; cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; CHX: cycloheximide; Co-IP: co-immunoprecipitation; CQ: chloroquine; EIF2A/eIF2α: eukaryotic translation initiation factor 2A; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; GFP: green fluorescent protein; HSPA5/GRP78: heat shock protein family A (Hsp70) member 5; HSV-1: herpes simplex virus type 1; IFIT1: interferon induced protein with tetratricopeptide repeats 1; IFNB1/IFN-β: interferon beta 1; IRF3: interferon regulatory factor 3; ISG15: ISG15 ubiquitin like modifier; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; NFKB/NF-κB: nuclear factor kappa B; NSP6: non-structural protein 6; Δ106–108: deletion of amino acids 106–108 in NSP6 of SARS-CoV-2; Δ105–107: deletion of amino acids 105–107 in NSP6 of SARS-CoV-2; RETREG1/FAM134B: reticulophagy regulator 1; RIGI/DDX58: RNA sensor RIG-I; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1.

Endoplasmic Reticulum Stress-Induced Autophagy Determines the Susceptibility of Melanoma Cells to Dabrafenib [Retraction

[This retracts the article DOI: 10.2147/DDDT.S112740.].

Endoplasmic reticulum chaperone GRP78 participates in fluoride-induced autophagy in LS8 cells by regulating the IRE1-TRAF2-JNK pathway.

Fluoride induces endoplasmic reticulum (ER) stress in ameloblasts, which is responsible for enamel mineralization disorder. Fluoride induces autophagy in ameloblasts, but the molecular mechanisms through which ameloblasts respond to fluoride-induced cellular stress and autophagy remain unclear. This study investigated ER stress-induced autophagy and the regulatory role of the ER molecular chaperone GRP78 in fluoride-induced autophagy in ameloblast LS8 cells. To explore the relationship between fluoride-induced ER stress and autophagy, we assessed changes in fluoride-induced autophagy in LS8 cells following overexpression and/or silencing of the ER stress molecular chaperone GRP78. We found that autophagy induced by fluoride was further increased after GRP78 overexpression in LS8 cells. Fluoride-induced autophagy was reduced in GRP78-silenced LS8 cells. Furthermore, we found that ER stress can regulate autophagy in fluoride-treated ameloblasts (LS8 cells) and that the GRP78/IRE1/TRAF2/JNK pathway is involved in the underlying regulation. Our study suggests that ER stress plays a role in fluoride-induced damage by inducing ameloblast autophagy.

MPA-capped CdTequantum dots induces endoplasmic reticulum stress-mediated autophagy and apoptosis through generation of reactive oxygen species in human liver normal cell and liver tumor cell

The rapid developments in nanotechnology have brought increased attention to the safety of Quantum Dots (QDs). Exploring their mechanisms of toxicity and characterizing their toxic effects in different cell lines will help us better understand and apply QDs appropriately. This study aims to elucidate the importance of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress-induced autophagy for CdTe QDs toxicity, that is, the importance of the nanoparticles in mediating cellular uptake and consequent intracellular stress effects inside the cell. The results of the study showed that cancer cells and normal cells have different cell outcomes as a result of intracellular stress effects. In normal human liver cells (L02), CdTe QDs leads to ROS generation and prolong ER stress. The subsequent autophagosome accumulation eventually triggers apoptosis by activating proapoptotic signaling pathways and the expression of proapoptotic Bax. In contrast, in human liver cancer cells (HepG2 cells), expression of UPR restrains proapoptotic signaling and downregulates Bax, and activated protective cellular autophagy, as a result of protecting these liver cancer cells from CdTe QDs-induced apoptosis. In summary, we assess the safety of CdTe QDs and recounted the molecular mechanism underlying its nanotoxicity in normal and cancerous cells. Notwithstanding, additional detailed studies on the deleterious effects of these nanoparticles in the organisms of interest are required to ensure low-risk application.

Abstract A088: Targeting endoplasmic reticulum stress-induced apoptosis to reduce health disparity in high-risk B-cell acute lymphoblastic leukemia in Hispanic/Latino children

Abstract B-cell Acute Lymphoblastic Leukemia (ALL) is the most common childhood malignancy. The death rate from B-ALL in Hispanic/Latino (H/L) is 40% higher than in non-Hispanic whites (NHW) after correcting socioeconomic factors. Deletion of one IKZF1 allele is highly increased H/L children, which provides a biological rationale for the worse prognosis of B-ALL in this population. The very high incidence (31% in all children and 65% in children ≥10 yrs) makes the deletion of one IKZF1 allele the most frequent genetic alteration that confers adverse prognosis in B-ALL in H/L children. The IKZF1 gene encodes a DNA-binding protein, IKAROS, which functions as a transcriptional regulator. Identification of IKAROS target genes in B-ALL of H/L children is essential to understand the specificity of B-ALL pathogenesis in those children and develop the targeted treatment to reduce the health disparity in survival for H/L children with B-ALL. Global DNA-binding analysis of primary B-ALL cells from H/L children showed that IKAROS binds to the promoter of eukaryotic elongation factor 2 kinase (eEF2K). eEF2K regulates protein synthesis, cell cycle progression and malignant transformation. The activity of eEF2K is increased in human malignancies, including B-ALL, and eEF2K is a critical regulator of endoplasmic reticulum (ER) stress-induced autophagy and apoptosis in tumor cells. The role of IKAROS in the regulation of eEF2K expression in B-ALL of H/L children was established using gain-of-function and loss-of-function experiments. Overexpression of IKZF1 in H/L B-ALL cells results in reduced expression of eEF2K, while IKZF1 knock-down results in increased transcription of eEF2K in H/L B-ALL. Since IKAROS function in leukemia is regulated by pro-oncogenic Casein Kinase 2 (CK2), we tested whether CK2 can control the ability of IKAROS to regulate the expression of eEF2K in H/L B-ALL. Increased expression of CK2 in H/L B-ALL results in increased expression of the eEF2K gene due to the loss of IKAROS binding to the promoter of the eEF2K genes. Inhibition of CK2 with shRNA and/or a specific CK2 inhibitor, CX-4945, restores IKAROS binding to promoter of eEF2K in high-risk B-ALL with deletion of one IKZF1 allele in H/L children. Restoration of IKAROS binding to promoter of eEF2K in high-risk B-ALL in H/L children results in reduced expression of this gene. This was associated with increased sensitivity to Akt inhibition by MK-2206. Combination treatment with CK2 inhibitor and MK-2206 showed a synergistic effect on B-ALL cells from H/L children. In summary, presented data demonstrate that IKAROS and CK2 regulate ER stress-induced apoptosis via regulation of eEF2K expression in high-risk B-ALL in Hispanic/Latino children. Results suggest that targeting ER stress-induced apoptosis in combination with CK2 inhibitors can be an efficient treatment to reduce the health disparity in survival for Hispanic/Latino children with B-ALL. Citation Format: Sinisa Dovat, Yali Ding, Dhimant Desai, Arati Sharma. Targeting endoplasmic reticulum stress-induced apoptosis to reduce health disparity in high-risk B-cell acute lymphoblastic leukemia in Hispanic/Latino children [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A088.

Abstract B029: Phenylacetaldehyde induces apoptosis through endoplasmic reticulum stress and potentiates the effect of 5-FU treatment in colorectal cancer

Abstract Introduction: Phenylacetaldehyde (PAA), a product of phenylalanine metabolism, is generated by microbiota and has demonstrated anticancer properties in breast cancer. As intestinal homeostasis is influenced by the gut microbiome, we investigated the effect of PAA on colorectal cancer (CRC). Methods: Serum PAA levels and feces microbiota from a test cohort of 30 CRC patients and 30 healthy control patients were analyzed by targeted GC-MS/MS and metagenomic sequencing. A validation cohort of 75 CRC patients and 53 healthy control patients was analyzed for PAA levels in serum. CRC cell lines and CRC-patient-derived organoids were cultured and treated with PAA alone or in combination with 5-fluorouracil (5-FU), then evaluated for viability, proliferation, cell cycle distribution, and cell death in vitro. The effect of PAA alone or in combination with 5-FU on tumor growth was also tested in vivo. We identified the mechanisms induced by PAA treatment using RNA sequencing, western blot, immunostaining, and ROS quantification assay. Results: PAA levels were significantly decreased in the circulation of CRC patients compared to healthy controls in our study population and the validation cohort. Metagenomic sequencing indicated the bacteria that positively correlated with PAA levels were significantly more abundant in healthy controls; while bacteria that negatively correlated with PAA were more abundant in CRC. In vitro, PAA inhibited the viability and colony formation of CRC cell lines as well as human-derived organoids in a concentration-dependent manner. Mechanistically, PAA treatment induced a P53-dependant G1 cell cycle arrest and cell death in HCT116 and RKO cell lines. An investigation by RNA sequencing and immunoblotting showed that PAA inhibits CRC by inducing endoplasmic reticulum stress-induced autophagy accompanied by downregulation in PI3K/AKT/mTOR and ERK pathways by generating reactive oxygen species. When combined with 5-FU, PAA enhanced the potency of 5-FU on viability, cell death, and cell cycle arrest by inducing DNA damage and tumor growth. Conclusions: The bacteria metabolite PAA increased CRC cell death by endoplasmic reticulum stress-induced autophagy and downregulation of the PI3K/AKT/mTOR and ERK pathways. PAA also potentiated the chemotherapeutic efficacy of 5-FU through induction of DNA damages. These findings warrant further exploration of PAA as a potential CRC biomarker and novel therapeutic agent. Citation Format: Sylvain J. Ferrandon, Cheng Kong, Joseph Fedro, Rami James Nabil Aoun, Zeneng Wang, Chureeporn Chitchumroonchokchai, Huanlong Qin, Steven Clinton, Matthew F. Kalady. Phenylacetaldehyde induces apoptosis through endoplasmic reticulum stress and potentiates the effect of 5-FU treatment in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B029.

Anti-SRP immune-mediated necrotizing myopathy: A critical review of current concepts.

Purpose of reviewThis review aims to describe clinical and histological features, treatment, and prognosis in patients with anti-signal recognition particle (SRP) autoantibodies positive immune-mediated necrotizing myopathy (SRP-IMNM) based on previous findings.Previous findingsAnti-SRP autoantibodies are specific in IMNM. Humoral autoimmune and inflammatory responses are the main autoimmune characteristics of SRP-IMNM. SRP-IMNM is clinically characterized by acute or subacute, moderately severe, symmetrical proximal weakness. Younger patients with SRP-IMNM tend to have more severe clinical symptoms. Patients with SRP-IMNM may be vulnerable to cardiac involvement, which ought to be regularly monitored and cardiac magnetic resonance imaging is the recommended detection method. The pathological features of SRP-IMNM are patchy or diffuse myonecrosis and myoregeneration accompanied by a paucity of inflammatory infiltrates. Endoplasmic reticulum stress-induced autophagy pathway and necroptosis are activated in skeletal muscle of SRP-IMNM. Treatment of refractory SRP-IMNM encounters resistance and warrants further investigation.SummaryAnti-SRP autoantibodies define a unique population of IMNM patients. The immune and non-immune pathophysiological mechanisms are involved in SRP-IMNM.

PERK/EIF2AK3 integrates endoplasmic reticulum stress-induced apoptosis, oxidative stress and autophagy responses in immortalised retinal pigment epithelial cells

Retinal pigment epithelium (RPE) performs essential functions for ensuring retinal homeostasis and is a key site for pathogenic changes leading to age-related macular degeneration (AMD). Compromised proteostasis in RPE results in ER stress and ER stress-dependent antioxidant, apoptosis and autophagic responses. ER stress induces the unfolded protein response (UPR) in which EIF2AK3, encoding the protein kinase RNA-like ER kinase (PERK), acts as a key regulator. Downregulated EIF2AK3 gene expression has recently been identified in AMD using human donor RPE, however the molecular mechanisms that integrate the various ER-mediated cellular pathways underpinning progressive RPE dysfunction in AMD have not been fully characterised. This study investigated the downstream effects of PERK downregulation in response to Brefeldin A (BFA)-induced ER stress in ARPE-19 cells. PERK downregulation resulted in increased ER stress and impaired apoptosis induction, antioxidant responses and autophagic flux. ARPE-19 cells were unable to efficiently induce autophagy following PERK downregulation and PERK presented a role in regulating the rate of autophagy induction. The findings support PERK downregulation as an integrative event facilitating dysregulation of RPE processes critical to cell survival known to contribute to AMD development and highlight PERK as a potential future therapeutic target for AMD.

Abstract 1830: Phenylacetaldehyde induces apoptosis through endoplasmic reticulum and potentiates the effect of 5-FU treatment in colorectal cancer cells

Abstract Introduction: Phenylacetaldehyde (PAA), a product of phenylalanine metabolism, is generated by microbiota and has demonstrated anticancer properties in breast cancer. As the gut microbiome influences intestinal homeostasis, we investigated the effects of PAA on colorectal cancer (CRC). Methods: Serum PAA levels and feces microbiota from 30 CRC patients and 30 healthy controls were analyzed by targeted GC-MS/MS and metagenomic sequencing. A validation cohort of 75 CRC patients and 53 healthy controls was analyzed for PAA level in serum. CRC cell lines and CRC-patient derived organoids were cultured and treated with PAA alone and in combination with 5-fluouracil (5-FU, standard chemotherapy used for CRC), then evaluated for viability, proliferation, cell cycle distribution, and cell death in vitro. We interrogated the mechanistic pathways induced by PAA treatment using RNA sequencing and western blot. Results: PAA levels were significantly decreased in the circulation of CRC patients compared to healthy controls in our study population and the validation cohort. Metagenomic sequencing indicated the bacteria that positively correlated with PAA levels were significantly more abundant in healthy controls; while bacteria that negatively correlated with PAA were more abundant in CRC. In vitro, PAA inhibited the viability and colony formation of CRC cell lines as well as human-derived organoids in a concentration-dependent manner. Mechanistically, PAA treatment induced a P53-dependant G1 cell cycle arrest and cell death in HCT116 and RKO cell lines. Proteomic analysis also demonstrated a downregulation in PI3K/AKT/mTOR and ERK pathways. Investigation by RNA sequencing showed that PAA inhibits CRC by inducing endoplasmic reticulum stress-induced autophagy. When combined with 5-FU, PAA enhanced the potency of 5-FU on viability, cell death, and cell cycle arrest by inducing DNA damage. Conclusions:The bacteria metabolite PAA increased CRC cell death by endoplasmic reticulum stress-induced autophagy and downregulation of the PI3K/AKT/mTOR and ERK pathways. PAA also potentiated chemotherapeutic efficacy of 5-FU through induction of DNA damages. These findings warrant further exploration of PAA as a potential CRC biomarker and novel therapeutic agent. Citation Format: Sylvain Ferrandon, Cheng Kong, Joseph Fedro, Rami-James Aoun, Chureeporn Chitchumroonchokchai, Steven Clinton, Matthew F. Kalady. Phenylacetaldehyde induces apoptosis through endoplasmic reticulum and potentiates the effect of 5-FU treatment in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1830.

Statement of Retraction: Isoginkgetin attenuates endoplasmic reticulum stress-induced autophagy of brain after ischemic reperfusion injury

This article refers to:Isoginkgetin attenuates endoplasmic reticulum stress-induced autophagy of brain after ischemic reperfusion injury

Revisited role of TRAF2 and TRAF2 C-terminal domain in endoplasmic reticulum stress-induced autophagy in HAP1 leukemia cells.

The scaffold protein Tumor Necrosis Factor Receptor-Associated Factor 2 (TRAF2) has been reported to play a key role in the endoplasmic reticulum (ER) stress-induced activation of c-Jun N-terminal Kinase (JNK) and hence autophagy. Autophagy is a highly conserved catabolic process, whose dysregulation is involved in the pathogenesis of various human diseases, including cancer. We investigated the involvement of TRAF2 in autophagy regulation in the human leukemic HAP1 cell line, under both basal and ER stress conditions. In TRAF2-knockout HAP1 cell line (KO), the basal autophagic flux was higher than in the parental cell line (WT). Moreover, tunicamycin-induced ER stress stimulated JNK activation and autophagy both in WT and KO HAP1. On the other hand, re-expression of a TRAF2 C-terminal fragment (residues ,310-501), in a TRAF2-KO cellular background, rendered HAP1 cells unable to activate both JNK and autophagy upon ER stress induction. Of note, this apparent dominant negative effect of the C-terminal fragment was observed even in the absence of the endogenous, full-length TRAF2 molecule. Furthermore, the expression of the C-terminal fragment resulted in both proteinkinaseB(AKT) pathway activation and increased resistance to the toxic effects induced by prolonged ER stress conditions. These findings indicate that TRAF2 is dispensable for the activation of both JNK and autophagy in HAP1 cells, while the TRAF2 C-terminal domain may play an autonomous role in regulating the cellular response to ER stress.

Endoplasmic Reticulum Stress Is Involved in Muscular Pathogenesis in Idiopathic Inflammatory Myopathies.

Objectives: Endoplasmic reticulum (ER) stress plays pivotal roles in the regulation of skeletal muscle damage and dysfunction in multiple disease conditions. We postulate the activation of ER stress in idiopathic inflammatory myopathies (IIM). Methods: Thirty-seven patients with immune-mediated necrotizing myopathy (IMNM), 21 patients with dermatomyositis (DM), 6 patients with anti-synthetase syndrome (ASS), and 10 controls were enrolled. The expression of ER stress-induced autophagy pathway was detected using histological sections, Western blot, and real-time quantitative Polymerase Chain Reaction. Results: ER stress-induced autophagy pathway was activated in biopsied muscle of patients with IMNM, DM, and ASS. The ER chaperone protein, glucose-regulated protein 78 (GRP78)/BiP expression in skeletal muscle correlated with autophagy, myofiber atrophy, myonecrosis, myoregeneration, and disease activity in IMNM. Conclusion: ER stress was involved in patients with IIM and correlates with disease activity in IMNM. ER stress response may be responsible for skeletal muscle damage and repair in IIM.

Atrial Natriuretic Peptide Attenuates Colitis via Inhibition of the cGAS-STING Pathway in Colonic Epithelial Cells.

Atrial Natriuretic Peptide (ANP) has known anti-inflammatory effects. However, the role of ANP in Ulcerative colitis (UC) remains unclear. This study aimed to explore the expression and function of ANP in UC, and its potential regulatory role in the stimulator of interferon genes (STING) pathway. Human colon biopsy and serum samples were collected between September 2018 and December 2019 at Wuhan Union Hospital. Levels of ANP and its receptors and STING pathway components were detected in people with UC and mice with dextran sulfate sodium (DSS)-induced colitis. These mice and HT-29 cells were treated with ANP and an agonist of the STING pathway. The level of inflammation, STING pathway, gut barrier, and endoplasmic reticulum (ER) stress-induced autophagy were measured. We found that the levels of ANP and its receptor decreased and the STING pathway activated statistically in people with UC and the mouse model of colitis. ANP treatment attenuated DSS-induced colitis and inhibited STING pathway phosphorylation in colonic tissue and epithelial cells. An interaction between cGAS and NPR-A was verified. ANP repaired the gut barrier and inhibited ER stress-induced autophagy via the STING pathway. ANP may thus alter colonic barrier function and regulate ER stress-induced autophagy as a promising therapy for UC.

Isoginkgetin attenuates endoplasmic reticulum stress-induced autophagy of brain after ischemic reperfusion injury

Isoginkgetin is characterized by properties of potent anticancer and anti-inflammation. To explore its effect on ischemic stroke, a rat model of ischemia/reperfusion (I/R) injury was established and induced by transient middle cerebral artery occlusion/reperfusion (MCAO/R). Different doses of isoginkgetin were intraperitoneally injected into each rat. Expressions of ER stress activation-related makers including phosphorylated inositol-requiring enzyme 1 (IRE1), phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), activating transcription factor-6 (ATF6), and two autophagy markers (ratio of LC3II/I and Beclin-1) were detected by western blot. Infarct volume, neurological deficits, and brain water content were detected. The results showed that ER stress and autophagy were activated by cerebral (I/R) injury, which could be effectively attenuated following pre-ischemia isoginkgetin administration. Moreover, autophagy induced by ER stress was triggered by the activation of PERK and IRE1 pathways. ER stress inhibitor (4-PBA) and ER related signaling inhibitors including PERK, GSK, IRE1, and DBSA markedly inhibited ER stress and autophagy induced by I/R. In addition, isoginkgetin markedly mitigated cerebral infarction, edema, neuronal apoptosis as well as neurological impairment induced by I/R injury, while tunicamycin (ER stress activator TM) and rapamycin (autophagy activator RAPA) could eliminate these lesions. This research identified a novel therapeutic agent isoginkgetin, which could effectively attenuate I/R injury by blocking autophagy induced by ER stress.

Retraction Statement.

Retraction Statement.

Sec62 Regulates Endoplasmic Reticulum Stress and Autophagy Balance to Affect Foot-and-Mouth Disease Virus Replication.

Endoplasmic reticulum (ER) stress-induced autophagy is closely associated with viral infection and propagation. However, the intrinsic link between ER stress, autophagy, and viral replication during foot-and-mouth disease virus (FMDV) infection is not fully elucidated. Our previous studies demonstrated that FMDV infection activated the ER stress-associated UPR of the PERK-eIF2a and ATF6 signaling pathway, whereas the IRE1a signaling was suppressed. We found that the activated-ATF6 pathway participated in FMDV-induced autophagy and FMDV replication, while the IRE1α pathway only affected FMDV replication. Further studies indicated that Sec62 was greatly reduced in the later stages of FMDV infection and blocked the activation of the autophagy-related IRE1α-JNK pathway. Moreover, it was also found that Sec62 promoted IRE1a phosphorylation and negatively regulated FMDV proliferation. Importantly, Sec62 may interact with LC3 to regulate ER stress and autophagy balance and eventually contribute to FMDV clearance via fusing with lysosomes. Altogether, these results suggest that Sec62 is a critical molecule in maintaining and recovering ER homeostasis by activating the IRE1α-JNK pathway and delivering autophagosome into the lysosome, thus providing new insights on FMDV-host interactions and novel antiviral therapies.

The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Neurodegeneration in Parkinson's Disease.

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, and it is characterized by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), as well as the presence of intracellular inclusions with α-synuclein as the main component in surviving DA neurons. Emerging evidence suggests that the imbalance of proteostasis is a key pathogenic factor for PD. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and autophagy, two major pathways for maintaining proteostasis, play important roles in PD pathology and are considered as attractive therapeutic targets for PD treatment. However, although ER stress/UPR and autophagy appear to be independent cellular processes, they are closely related to each other. In this review, we focused on the roles and molecular cross-links between ER stress/UPR and autophagy in PD pathology. We systematically reviewed and summarized the most recent advances in regulation of ER stress/UPR and autophagy, and their cross-linking mechanisms. We also reviewed and discussed the mechanisms of the coexisting ER stress/UPR activation and dysregulated autophagy in the lesion regions of PD patients, and the underlying roles and molecular crosslinks between ER stress/UPR activation and the dysregulated autophagy in DA neurodegeneration induced by PD-associated genetic factors and PD-related neurotoxins. Finally, we indicate that the combined regulation of ER stress/UPR and autophagy would be a more effective treatment for PD rather than regulating one of these conditions alone.