bims-unfpre 2023-11-12 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023–11–12
eleven papers selected by
Susan Logue, University of Manitoba

Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells.
Stress-induced β cell early senescence confers protection against type 1 diabetes.
IRE1-mediated degradation of pre-miR-301a promotes apoptosis through upregulation of GADD45A.
Modulation of endoplasmic reticulum stress response pathways by respiratory viruses.
Identification of endoplasmic reticulum stress-related signature characterizes the tumor microenvironment and predicts prognosis in lung adenocarcinoma.
Differential Ire1 determines loser cell fate in tumor-suppressive cell competition.
HRS mediates tumor immune evasion by regulating proteostasis-associated interferon pathway activation.
TOLLIP acts as a cargo adaptor to promote lysosomal degradation of aberrant ER membrane proteins.
TTC17 is an endoplasmic reticulum resident TPR-containing adaptor protein.
TMTC4 is a hair-cell-specific human deafness gene.
IRE1α/XBP-1 promotes β-catenin signaling activation of airway epithelium in lipopolysaccharide-induced acute lung injury.

Cell Chem Biol. 2023 Oct 26. pii: S2451-9456(23)00367-7. [Epub ahead of print]

Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells.

Valerie Perea, Kelsey R Baron, Vivian Dolina, Giovanni Aviles, Grace Kim, Jessica D Rosarda, Xiaoyan Guo, Martin Kampmann, R Luke Wiseman.

  The integrated stress response (ISR) comprises the eIF2α kinases PERK, GCN2, HRI, and PKR, which induce translational and transcriptional signaling in response to diverse insults. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activation of compensatory eIF2α kinases to rescue ISR signaling and promote mitochondrial adaptation in PERK-deficient cells. We show that the HRI activator BtdCPU and GCN2 activator halofuginone promote ISR signaling and rescue ER stress sensitivity in PERK-deficient cells. However, BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and activation of the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and adaptive mitochondrial respiration, mimicking regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK signaling and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly selective ISR activators.

Keywords:  ISR; UPR; integrated stress response; pharmacologic activator; stress-responsive signaling pathway; unfolded protein response

DOI:  https://doi.org/10.1016/j.chembiol.2023.10.006
Cell Metab. 2023 Nov 05. pii: S1550-4131(23)00383-2. [Epub ahead of print]

Stress-induced β cell early senescence confers protection against type 1 diabetes.

Hugo Lee, Gulcan Semra Sahin, Chien-Wen Chen, Shreyash Sonthalia, Sandra Marín Cañas, Hulya Zeynep Oktay, Alexander T Duckworth, Gabriel Brawerman, Peter J Thompson, Maria Hatzoglou, Decio L Eizirik, Feyza Engin.

  During the progression of type 1 diabetes (T1D), β cells are exposed to significant stress and, therefore, require adaptive responses to survive. The adaptive mechanisms that can preserve β cell function and survival in the face of autoimmunity remain unclear. Here, we show that the deletion of the unfolded protein response (UPR) genes Atf6α or Ire1α in β cells of non-obese diabetic (NOD) mice prior to insulitis generates a p21-driven early senescence phenotype and alters the β cell secretome that significantly enhances the leukemia inhibitory factor-mediated recruitment of M2 macrophages to islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause the resolution of islet inflammation, the removal of terminally senesced β cells, the reduction of β cell apoptosis, and protection against T1D. We further demonstrate that the p21-mediated early senescence signature is conserved in the residual β cells of T1D patients. Our findings reveal a previously unrecognized link between β cell UPR and senescence that, if leveraged, may represent a novel preventive strategy for T1D.

Keywords:  ER stress; M2 macrophage; NOD mice; UPR; immune surveillance; secretome; senescence; type 1 diabetes; β cells

DOI:  https://doi.org/10.1016/j.cmet.2023.10.014
Cell Commun Signal. 2023 Nov 09. 21(1): 322

IRE1-mediated degradation of pre-miR-301a promotes apoptosis through upregulation of GADD45A.

Magdalena Gebert, Sylwia Bartoszewska, Lukasz Opalinski, James F Collawn, Rafał Bartoszewski.

  The unfolded protein response is a survival signaling pathway that is induced during various types of ER stress. Here, we determine IRE1's role in miRNA regulation during ER stress. During induction of ER stress in human bronchial epithelial cells, we utilized next generation sequencing to demonstrate that pre-miR-301a and pre-miR-106b were significantly increased in the presence of an IRE1 inhibitor. Conversely, using nuclear-cytosolic fractionation on ER stressed cells, we found that these pre-miRNAs were decreased in the nuclear fractions without the IRE1 inhibitor. We also found that miR-301a-3p targets the proapoptotic UPR factor growth arrest and DNA-damage-inducible alpha (GADD45A). Inhibiting miR-301a-3p levels or blocking its predicted miRNA binding site in GADD45A's 3' UTR with a target protector increased GADD45A mRNA expression. Furthermore, an elevation of XBP1s expression had no effect on GADD45A mRNA expression. We also demonstrate that the introduction of a target protector for the miR-301a-3p binding site in GADD45A mRNA during ER stress promoted cell death in the airway epithelial cells. In summary, these results indicate that IRE1's endonuclease activity is a two-edged sword that can splice XBP1 mRNA to stabilize survival or degrade pre-miR-301a to elevate GADD45A mRNA expression to lead to apoptosis. Video Abstract.

Keywords:  Cell fate; ER stress; IRE1; UPR; miRNA; microRNA

DOI:  https://doi.org/10.1186/s12964-023-01349-0
Crit Rev Microbiol. 2023 Nov 07. 1-19

Modulation of endoplasmic reticulum stress response pathways by respiratory viruses.

Kyle L Macauslane, Cassandra L Pegg, Kirsty R Short, Benjamin L Schulz.

  Acute respiratory infections (ARIs) are amongst the leading causes of death and disability, and the greatest burden of disease impacts children, pregnant women, and the elderly. Respiratory viruses account for the majority of ARIs. The unfolded protein response (UPR) is a host homeostatic defence mechanism primarily activated in response to aberrant endoplasmic reticulum (ER) resident protein accumulation in cell stresses including viral infection. The UPR has been implicated in the pathogenesis of several respiratory diseases, as the respiratory system is particularly vulnerable to chronic and acute activation of the ER stress response pathway. Many respiratory viruses therefore employ strategies to modulate the UPR during infection, with varying effects on the host and the pathogens. Here, we review the specific means by which respiratory viruses affect the host UPR, particularly in association with the high production of viral glycoproteins, and the impact of UPR activation and subversion on viral replication and disease pathogenesis. We further review the activation of UPR in common co-morbidities of ARIs and discuss the therapeutic potential of modulating the UPR in virally induced respiratory diseases.

Keywords:  Respiratory virus infection; coronavirus; glycoproteins; influenza virus; respiratory syncytial virus; unfolded protein response; viral replication; virus-host biology

DOI:  https://doi.org/10.1080/1040841X.2023.2274840
Sci Rep. 2023 Nov 09. 13(1): 19462

Identification of endoplasmic reticulum stress-related signature characterizes the tumor microenvironment and predicts prognosis in lung adenocarcinoma.

Li Wan, Zhike Chen, Jian Yang, Gaotian Wu, Yao Xu, Jian Cui, Xueping Zhao.

Lung adenocarcinoma (LUAD) remains one of the most lethal malignancies worldwide, with a high mortality rate and unfavorable prognosis. Endoplasmic reticulum (ER) stress is a key regulator of tumour growth, metastasis, and the response to chemotherapy, targeted therapies and immune response. It acts via responding to misfolded proteins and triggering abnormal activation of ER stress sensors and downstream signalling pathways. Notably, the expression patterns of ER-stress-related-genes (ERSRGs) are indicative of survival outcomes, especially in the context of immune infiltration. Through consensus clustering of prognosis-associated ERSRGs, we delineated two distinct LUAD subtypes: Cluster 1 and Cluster 2. Comprehensive analyses revealed significant disparities between these subtypes in terms of prognosis, immune cell infiltration, and tumor progression. Leveraging the robustness of LASSO regression and Multivariate stepwise regression, we constructed and validated an ER Stress-associated risk signature for LUAD. This signature underwent assessments for its prognostic value, correlation with clinical attributes, and interaction within the tumour immune microenvironment. By integrating this signature with multivariate cox analysis of distinct pathological stages, we devised an enhanced nomogram, validated through various statistical metrics, with an area under the curve for overall survival at 1, 3, and 5 years post-diagnosis being 0.79, 0.80, and 0.81, respectively. In conclusion, our findings introduce a composite signature of 11 pivotal ERSRGs, holding promise as a potent prognostic tool for LUAD, and offering insights for immunotherapeutic and targeted intervention strategies.

DOI: https://doi.org/10.1038/s41598-023-45690-3
Cell Rep. 2023 Nov 03. pii: S2211-1247(23)01315-3. [Epub ahead of print]42(11): 113303

Differential Ire1 determines loser cell fate in tumor-suppressive cell competition.

Jiadong Zheng, Yifan Guo, Changyi Shi, Shuai Yang, Wenyan Xu, Xianjue Ma.

  Tumor-suppressive cell competition (TSCC) is a conserved surveillance mechanism in which neighboring cells actively eliminate oncogenic cells. Despite overwhelming studies showing that the unfolded protein response (UPR) is dysregulated in various tumors, it remains debatable whether the UPR restrains or promotes tumorigenesis. Here, using Drosophila eye epithelium as a model, we uncover a surprising decisive role of the Ire1 branch of the UPR in regulating cell polarity gene scribble (scrib) loss-induced TSCC. Both mutation and hyperactivation of Ire1 accelerate elimination of scrib clones via inducing apoptosis and autophagy, respectively. Unexpectedly, relative Ire1 activity is also crucial for determining loser cell fate, as dysregulating Ire1 signaling in the surrounding healthy cells reversed the "loser" status of scrib clones by decreasing their apoptosis. Furthermore, we show that Ire1 is required for cell competition in mammalian cells. Together, these findings provide molecular insights into scrib-mediated TSCC and highlight Ire1 as a key determinant of loser cell fate.

Keywords:  CP: Cell biology; Drosophila; E-cad; Ire1; UPR; apoptosis; autophagy; cell competition; scribble; tumor

DOI:  https://doi.org/10.1016/j.celrep.2023.113303
Cell Rep. 2023 Nov 08. pii: S2211-1247(23)01364-5. [Epub ahead of print]42(11): 113352

HRS mediates tumor immune evasion by regulating proteostasis-associated interferon pathway activation.

Wei Zhang, Jiegang Yang, Beike Wang, Youtao Lu, Jingbo Yang, Wenqun Zhong, Ziyan Yu, Zhiyuan Qin, Bolin Xiao, Kuiming Wang, Yi Y Ma, Ravi Amaravadi, Meenhard Herlyn, Junhyong Kim, Xiaowei Xu, Wei Guo.

  By sorting receptor tyrosine kinases into endolysosomes, the endosomal sorting complexes required for transport (ESCRTs) are thought to attenuate oncogenic signaling in tumor cells. Paradoxically, ESCRT members are upregulated in tumors. Here, we show that disruption of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), a pivotal ESCRT component, inhibited tumor growth by promoting CD8+ T cell infiltration in melanoma and colon cancer mouse models. HRS ablation led to misfolded protein accumulation and triggered endoplasmic reticulum (ER) stress, resulting in the activation of the type I interferon pathway in an inositol-requiring enzyme-1α (IRE1α)/X-box binding protein 1 (XBP1)-dependent manner. HRS was upregulated in tumor cells with high tumor mutational burden (TMB). HRS expression associates with the response to PD-L1/PD-1 blockade therapy in melanoma patients with high TMB tumors. HRS ablation sensitized anti-PD-1 treatment in mouse melanoma models. Our study shows a mechanism by which tumor cells with high TMB evade immune surveillance and suggests HRS as a promising target to improve immunotherapy.

Keywords:  CP: Cancer; CP: Immunology; ▪▪▪

DOI:  https://doi.org/10.1016/j.celrep.2023.113352
EMBO J. 2023 Nov 06. e114272

TOLLIP acts as a cargo adaptor to promote lysosomal degradation of aberrant ER membrane proteins.

Yuki Hayashi, Sho Takatori, Waleed Y Warsame, Taisuke Tomita, Takao Fujisawa, Hidenori Ichijo.

  Endoplasmic reticulum (ER) proteostasis is maintained by various catabolic pathways. Lysosomes clear entire ER portions by ER-phagy, while proteasomes selectively clear misfolded or surplus aberrant proteins by ER-associated degradation (ERAD). Recently, lysosomes have also been implicated in the selective clearance of aberrant ER proteins, but the molecular basis remains unclear. Here, we show that the phosphatidylinositol-3-phosphate (PI3P)-binding protein TOLLIP promotes selective lysosomal degradation of aberrant membrane proteins, including an artificial substrate and motoneuron disease-causing mutants of VAPB and Seipin. These cargos are recognized by TOLLIP through its misfolding-sensing intrinsically disordered region (IDR) and ubiquitin-binding CUE domain. In contrast to ER-phagy receptors, which clear both native and aberrant proteins by ER-phagy, TOLLIP selectively clears aberrant cargos by coupling them with the PI3P-dependent lysosomal trafficking without promoting bulk ER turnover. Moreover, TOLLIP depletion augments ER stress after ERAD inhibition, indicating that TOLLIP and ERAD cooperatively safeguard ER proteostasis. Our study identifies TOLLIP as a unique type of cargo-specific adaptor dedicated to the clearance of aberrant ER cargos and provides insights into molecular mechanisms underlying lysosome-mediated quality control of membrane proteins.

Keywords:  ER-phagy; TOLLIP; cargo adaptor; intrinsically disordered region; lysosome

DOI:  https://doi.org/10.15252/embj.2023114272
J Biol Chem. 2023 Nov 08. pii: S0021-9258(23)02478-X. [Epub ahead of print] 105450

TTC17 is an endoplasmic reticulum resident TPR-containing adaptor protein.

Nathan P Canniff, Jill B Graham, Kevin P Guay, Daniel A Lubicki, Stephen J Eyles, Jennifer N Rauch, Daniel N Hebert.

  Protein folding, quality control, maturation, and trafficking are essential processes for proper cellular homeostasis. Around one third of the human proteome is targeted to the endoplasmic reticulum (ER), the organelle that serves as entrance into the secretory pathway. Successful protein trafficking is paramount for proper cellular function and to that end there are many ER resident proteins that ensure efficient secretion. Here, biochemical and cell biological analysis was used to determined that TTC17 is a large, soluble, ER localized protein that plays an important role in secretory trafficking. Transcriptional analysis identified the predominantly expressed protein isoform of TTC17 in various cell lines. Further, TTC17 localizes to the ER and interacts with a wide variety of chaperones and co-chaperones normally associated with ER protein folding, quality control, and maturation processes. TTC17 was found to be significantly upregulated by ER stress and through the creation and use of TTC17-/- cell lines, quantitative mass spectrometry identified secretory pathway wide trafficking defects in the absence of TTC17. Notably, trafficking of IGF1R, GPNMB, CLU and UGGT1 were significantly altered in H4 neuroglioma cells. This study defines a novel ER trafficking factor and provides insight into the protein-protein assisted trafficking in the early secretory pathway.

Keywords:  ER quality control; TPR; UGGT; adaptor protein; cell compartmentalization; chaperone; endoplasmic reticulum (ER); endoplasmic reticulum stress (ER stress); intracellular trafficking; molecular chaperones; protein trafficking; secretion

DOI:  https://doi.org/10.1016/j.jbc.2023.105450
JCI Insight. 2023 Nov 09. pii: e172665. [Epub ahead of print]

TMTC4 is a hair-cell-specific human deafness gene.

Jiang Li, Byung Yoon Choi, Yasmin Eltawil, Noura Ismail Mohamad, Yesai Park, Ian R Matthews, Jin-Hee Han, Bong Jik Kim, Elliott H Sherr, Dylan K Chan.

  Transmembrane and tetratricopeptide repeat 4 (Tmtc4) is a recently described novel deafness gene in mice. Tmtc4-knockout mice have rapidly progressive postnatal hearing loss due to overactivation of the unfolded protein response (UPR); however, the cellular basis and human relevance of Tmtc4-associated hearing loss in the cochlea was not heretofore appreciated. We created a hair-cell-specific conditional knockout mouse that phenocopies the constitutive knockout with postnatal onset deafness, demonstrating that Tmtc4 is a hair-cell specific deafness gene. Furthermore, we identified a human family in which Tmtc4 variants segregate with adult-onset progressive hearing loss. Lymphoblastoid cells derived from multiple affected and unaffected family members, as well as human embryonic kidney cells engineered to harbor each of the variants, demonstrated that the human Tmtc4 variants confer hypersensitivity of the UPR towards apoptosis. These findings provide evidence that TMTC4 is a deafness gene in humans and further implicate the UPR in progressive hearing loss.

Keywords:  Cell stress; Genetic diseases; Mouse models; Otology

DOI:  https://doi.org/10.1172/jci.insight.172665
Pulm Pharmacol Ther. 2023 Nov 05. pii: S1094-5539(23)00075-5. [Epub ahead of print] 102263

IRE1α/XBP-1 promotes β-catenin signaling activation of airway epithelium in lipopolysaccharide-induced acute lung injury.

Hailing Zhang, Jiehong Li, Xilong Wang, Kai Wang, JianPeng Xie, Guanjin Chen, Yijian Li, Kai Zhong, Jiahui Li, Xin Chen.

   BACKGROUND: Acute lung injury (ALI), along with the more severe condition--acute respiratory distress syndrome (ARDS), is a major cause of respiratory failure in critically ill patients with high morbidity and mortality. Inositol-requiring protein 1α (IRE1α)/X box protein-1 (XBP1) pathway was proved to regulate lipopolysaccharide (LPS)-induced lung injury and inflammation. Yet, its role on epithelial β-catenin in LPS-induced ALI remains to be elucidated.
METHODS: LPS-induced models were generated in mice (5 mg/kg) and Beas-2B cells (200 μg/mL). Two selective antagonists of IRE1α (4μ8c and STF-083010) were respectively given to LPS-exposed mice and cultured cells.
RESULTS: Up-regulated expression of endoplasmic reticulum (ER) stress markers immunoglobulin-binding protein (BIP) and spliced X box protein-1(XBP-1s) was detected after LPS exposure. Besides, LPS also led to a down-regulated total β-catenin level in the lung and Beas-2B cells, with decreased membrane distribution as well as increased cytoplasmic and nuclear accumulation, paralleled by extensively up-regulated downstream targets of the Wnt/β-catenin signaling. Treatment with either 4μ8c or STF-083010 not only significantly attenuated LPS-induced lung injury and inflammation, but also recovered β-catenin expression in airway epithelia, preserving the adhesive function of β-catenin while blunting its signaling activity.
CONCLUSION: These results illustrated that IRE1α/XBP1 pathway promoted the activation of airway epithelial β-catenin signaling in LPS-induced ALI.

Keywords:  Acute lung injury; Airway epithelium; IRE1α/XBP1; β-catenin

DOI:  https://doi.org/10.1016/j.pupt.2023.102263