Cell Stress最新文献

{"title":"Ribosome traffic jam in neurodegeneration: decoding hurdles in Huntington disease.","authors":"Srinivasa Subramaniam","doi":"10.15698/cst2021.06.251","DOIUrl":"https://doi.org/10.15698/cst2021.06.251","url":null,"abstract":"<p><p>A ribosome typically moves at a particular rate on a given mRNA transcript to decode the nucleic acid information required to synthesize proteins. The speed and directionality of the ribosome movements during mRNA translation are determined by the mRNA sequence and structure and by various decoding factors. However, the molecular mechanisms of this remarkable movement during protein synthesis, or its relevance in brain disorders, remain unknown. Recent studies have indicated that defects in protein synthesis occur in various neurodegenerative diseases, but the mechanistic details are unclear. This is a major problem because identifying the factors that determine protein synthesis defects may offer new avenues for developing therapeutic remedies for currently incurable diseases like neurodegenerative disorders. Based on our recent study (Eshraghi <i>et al.</i>, Nat Commun 12(1):1461; doi: 10.1038/s41467-021-21637-y), this short commentary will review the mechanistic understanding of Huntingtin (HTT)-mediated ribosome stalling indicating that central defects in protein synthesis in Huntington disease (HD) are orchestrated by jamming of ribosomes on mRNA transcripts.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2021-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39092560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The evolution of the concept of stress and the framework of the stress system.","authors":"Siyu Lu, Fang Wei, Guolin Li","doi":"10.15698/cst2021.06.250","DOIUrl":"10.15698/cst2021.06.250","url":null,"abstract":"<p><p>Stress is a central concept in biology and has now been widely used in psychological, physiological, social, and even environmental fields. However, the concept of stress was cross-utilized to refer to different elements of the stress system including stressful stimulus, stressor, stress response, and stress effect. Here, we summarized the evolution of the concept of stress and the framework of the stress system. We find although the concept of stress is developed from Selye's \"general adaptation syndrome\", it has now expanded and evolved significantly. Stress is now defined as a state of homeostasis being challenged, including both system stress and local stress. A specific stressor may potentially bring about specific local stress, while the intensity of stress beyond a threshold may commonly activate the hypothalamic-pituitary-adrenal axis and result in a systematic stress response. The framework of the stress system indicates that stress includes three types: sustress (inadequate stress), eustress (good stress), and distress (bad stress). Both sustress and distress might impair normal physiological functions and even lead to pathological conditions, while eustress might benefit health through hormesis-induced optimization of homeostasis. Therefore, an optimal stress level is essential for building biological shields to guarantee normal life processes.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2021-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39092559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coping with the calcium overload caused by cell injury: ER to the rescue.","authors":"Goutam Chandra,&nbsp;Davi A G Mázala,&nbsp;Jyoti K Jaiswal","doi":"10.15698/cst2021.05.249","DOIUrl":"https://doi.org/10.15698/cst2021.05.249","url":null,"abstract":"<p><p>Cells maintain their cytosolic calcium (Ca²⁺) in nanomolar range and use controlled increase in Ca²⁺ for intracellular signaling. With the extracellular Ca²⁺ in the millimolar range, there is a steep Ca²⁺ gradient across the plasma membrane (PM). Thus, injury that damages PM, leads to a cytosolic Ca²⁺ overload, which helps activate PM repair (PMR) response. However, in order to survive, the cells must cope with the Ca²⁺ overload. In a recent study (Chandra <i>et al.</i> J Cell Biol, doi: 10.1083/jcb.202006035) we have examined how cells cope with injury-induced cytosolic Ca²⁺ overload. By monitoring Ca²⁺ dynamics in the cytosol and endoplasmic reticulum (ER), we found that PM injury-triggered increase in cytosolic Ca²⁺ is taken up by the ER. Pharmacological inhibition of ER Ca²⁺ uptake interferes with this process and compromises the repair ability of the injured cells. Muscle cells from patients and mouse model for the muscular dystrophy showed that lack of Anoctamin 5 (ANO5)/Transmembrane protein 16E (TMEM16E), an ER-resident putative Ca²⁺-activated chloride channel (CaCC), are poor at coping with cytosolic Ca²⁺ overload. Pharmacological inhibition of CaCC and lack of ANO5, both prevent Ca²⁺ uptake into ER. These studies identify a requirement of Cl^- uptake by the ER in sequestering injury-triggered cytosolic Ca²⁺ increase in the ER. Further, these studies show that ER helps injured cells cope with Ca²⁺ overload during PMR, lack of which contributes to muscular dystrophy due to mutations in the ANO5 protein.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2021-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38979703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular mechanisms linking cancers to obesity.","authors":"Xiao-Zheng Liu,&nbsp;Line Pedersen,&nbsp;Nils Halberg","doi":"10.15698/cst2021.05.248","DOIUrl":"https://doi.org/10.15698/cst2021.05.248","url":null,"abstract":"<p><p>Obesity is epidemiologically linked to 13 forms of cancer. The local and systemic obese environment is complex and likely affect tumors through multiple avenues. This includes modulation of cancer cell phenotypes and the composition of the tumor microenvironment. A molecular understanding of how obesity links to cancer holds promise for identifying candidate genes for targeted therapy for obese cancer patient. Herein, we review both the cell-autonomous and non-cell-autonomous mechanisms linking obesity and cancer as well as provide an overview of the mouse model systems applied to study this.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2021-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38979704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibitory DAMPs in immunogenic cell death and its clinical implications.","authors":"Kazukuni Hayashi,&nbsp;Fotis Nikolos,&nbsp;Keith S Chan","doi":"10.15698/cst2021.04.247","DOIUrl":"https://doi.org/10.15698/cst2021.04.247","url":null,"abstract":"<p><p>Dying (or dead) cells are increasingly recognized to impose significant biological influence within their tissues of residence-exerting paracrine effects through proteins and metabolites that are expressed or secreted during cellular demise. For example, certain molecules function as potent mitogens, promoting the repopulation of neighboring epithelial cells. And other myriad of factors-classified as damage-associated molecular patterns (DAMPs)-function as \"find me\" (attractant), \"eat me\" (engulfment), or \"danger\" (activation) signals for recruiting and activating effector immune cells (e.g., dendritic cells) to initiate inflammation. Since the discovery of immunogenic cell death (ICD), the current dogma posits DAMPs as immunological adjuvants for innate immune cell mobilization and activation, which ultimately leads to the antitumoral cross-priming of CD8⁺ T cells. However, what is currently unknown is how these immunostimulatory DAMPs are counteracted to avoid immune-overactivation. Our recent work builds on these fundamentals and introduces prostaglandin E₂ (PGE₂) as an 'inhibitory' DAMP-a new variable to the ICD equation. Prostaglandin E₂ functions as an immunosuppressive counterpoise of adjuvant DAMPs; and thus, mechanistically precludes ICD. Furthermore, the long-debated immunogenicity of gemcitabine chemotherapy was revealed to be contingent on inhibitory DAMP blockade and not due to its inability to promote DAMP expression (i.e., calreticulin) as previously reported. These findings were intriguing. First, despite the presence of gemcitabine-induced hallmark DAMPs, the inhibitory DAMP (i.e., PGE₂) was sufficient to hinder the ICD-induced antitumoral immune response (Fig. 1a). And second, rather than pharmacologically substantiating immunostimulatory DAMPs as conventionally approached, the mitigation of the inhibitory DAMP-tipping the immunostimulatory and inhibitory DAMP balance in favor of immunostimulatory DAMPs-was sufficient to render the cell death immunogenic and converted gemcitabine into an ICD-inducing therapy (Fig. 1b). In this microreview, we extrapolate our findings and implicate the value of inhibitory DAMP(s) in drug discovery, its use for clinical prognosis, and as target(s) for therapeutic intervention.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2021-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25574052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles of phosphatidyl inositol 3 kinase gamma (PI3Kγ) in respiratory diseases.","authors":"Valentina Sala,&nbsp;Angela Della Sala,&nbsp;Alessandra Ghigo,&nbsp;Emilio Hirsch","doi":"10.15698/cst2021.04.246","DOIUrl":"https://doi.org/10.15698/cst2021.04.246","url":null,"abstract":"<p><p>Phosphatidyl inositol 3 kinase gamma (PI3Kγ) is expressed in all the cell types that are involved in airway inflammation and disease, including not only leukocytes, but also structural cells, where it is expressed at very low levels under physiological conditions, while is significantly upregulated after stress. In the airways, PI3Kγ behaves as a trigger or a controller, depending on the pathological context. In this review, the contribution of PI3Kγ in a plethora of respiratory diseases, spanning from acute lung injury, pulmonary fibrosis, asthma, cystic fibrosis and response to both bacterial and viral pathogens, will be commented.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2021-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25574051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spermidine supplementation in rare translation-associated disorders.","authors":"Andreas Zimmermann, Didac Carmona-Gutierrez, Frank Madeo","doi":"10.15698/cst2021.03.243","DOIUrl":"10.15698/cst2021.03.243","url":null,"abstract":"<p><p>The polyamine spermidine is essential for protein translation in eukaryotes, both as a substrate for the hypusination of the translation initiation factor eIF5A as well as general translational fidelity. Dwindling spermidine levels during aging have been implicated in reduced immune cell function through insufficient eIF5A hypusination, which can be restored by external supplementation. Recent findings characterize a group of novel Mendelian disorders linked to <i>EIF5A</i> missense and nonsense variants that cause protein translation defects. In model organisms that recapitulate these mutations, spermidine supplementation was able to alleviate at least some of the concomitant protein translation defects. Here, we discuss the role of spermidine in protein translation and possible therapeutic avenues for translation-associated disorders.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2021-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25451089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting FBXO44/SUV39H1 elicits tumor cell-specific DNA replication stress and viral mimicry.","authors":"Jia Z Shen,&nbsp;Charles Spruck","doi":"10.15698/cst2021.03.245","DOIUrl":"https://doi.org/10.15698/cst2021.03.245","url":null,"abstract":"<p><p>Repetitive elements (REs) are normally transcriptionally silenced in somatic cells by repressive epigenetic modifications, which are thought to include DNA methylation and histone modifications such as deacetylation, H3K9me3, and H4K20me3. Although, it is unclear how RE silencing is maintained through DNA replication cycles in rapidly growing cancer cells. On the other hand, the reactivation of endogenous retroelements beyond a threshold level of tolerance in cancer cells, such as by treatment with DNA demethylating agents or HDAC or LSD1 inhibitors, can induce viral mimicry responses that augment certain cancer therapies, including immunotherapy. However, these agents can also affect normal cells presenting obvious side effects. Therefore, uncovering cancer cell-specific RE silencing mechanisms could provide a basis for the development of a new generation of cancer immunotherapy drugs. In our study (Shen <i>et al.</i> (2020), Cell, doi: 10.1016/j.cell.2020.11.042), through a high-content RNAi screen we identified FBXO44 as a key regulator of H3K9me3-mediated transcriptional silencing of REs in cancer cells. Inhibition of FBXO44 or its co-factor SUV39H1 stimulated antiviral pathways and interferon (IFN) signaling and induced replication stress and DNA double-strand breaks (DSBs) in cancer cells, leading to restricted tumor growth and synergy with anti-PD-1 therapy (Figure 1). Figure 1FIGURE 1: Graphical representation of this study.FBXO44/SUV39H1 targeting activates REs that elicit DNA replication stress and viral mimicry in cancer cells, leading to tumor growth arrest and enhanced immunotherapy response.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2021-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25446418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The OFD1 protein is a novel player in selective autophagy: another tile to the cilia/autophagy puzzle.","authors":"Manuela Morleo,&nbsp;Brunella Franco","doi":"10.15698/cst2021.03.244","DOIUrl":"https://doi.org/10.15698/cst2021.03.244","url":null,"abstract":"<p><p>The autophagy-lysosomal pathway is one of the main degradative routes which cells use to balance sources of energy. A number of proteins orchestrate the formation of autophagosomes, membranous organelles instrumental in autophagy. Selective autophagy, involving the recognition and removal of specific targets, is mediated by autophagy receptors, which recognize cargos and the autophagosomal membrane protein LC3 for lysosomal degradation. Recently, bidirectional crosstalk has emerged between autophagy and primary cilia, microtubule-based sensory organelles extending from cells and anchored by the basal body, derived from the mother centriole of the centrosome. The molecular mechanisms underlying the direct role of autophagic proteins in cilia biology and, conversely, the impact of this organelle in autophagy remains elusive. Recently, we uncovered the molecular mechanism by which the centrosomal/basal body protein OFD1 controls the LC3-mediated autophagic cascade. In particular, we demonstrated that OFD1 acts as a selective autophagy receptor by regulating the turnover of unc-51-like kinase (ULK1) complex, which plays a crucial role in the initiation steps of autophagosome biogenesis. Moreover, we showed that patients with a genetic condition caused by mutations in <i>OFD1</i> and associated with cilia dysfunction, display excessive autophagy and we demonstrated that autophagy inhibition significantly ameliorates the renal cystic phenotype in a conditional mouse model recapitulating the features of the disease (Morleo et al. 2020, EMBO J, doi: 10.15252/embj.2020105120). We speculate that abnormal autophagy may underlie some of the clinical manifestations observed in the disorders ascribed to cilia dysfunction.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2021-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25446417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innate RIG-I signaling restores antigen presentation in tumors and overcomes T cell resistance.","authors":"Beatrice Thier,&nbsp;Annette Paschen","doi":"10.15698/cst2021.02.242","DOIUrl":"https://doi.org/10.15698/cst2021.02.242","url":null,"abstract":"<p><p>In recent years, therapy with immune modulating antibodies, termed immune checkpoint blockade (ICB), has revolutionized the treatment of advanced metastatic melanoma, yielding long-lasting clinical responses in a subgroup of patients. But despite this remarkable progress, resistance to therapy represents a major clinical challenge. ICB efficacy is critically dependent on cytotoxic CD8+ T cells targeting tumor cells in an HLA class I (HLA-I) antigen-dependent manner. Transcriptional suppression of the HLA-I antigen processing and presentation machinery (HLA-I APM) in melanoma cells leads to HLA-I-low/-negative tumor cell phenotypes escaping CD8+ T cell recognition and contributing to ICB resistance. In general, HLA-I-low/-negative tumor cells can be re-sensitized to T cells by interferons (IFN), augmenting HLA-I APM expression. However, this mechanism fails when melanoma cells acquire resistance to IFN, which recently turned out as a key resistance mechanism in ICB, besides HLA-I APM suppression. Seeking for a strategy to overcome these barriers, we identified a novel mechanism that restores HLA-I antigen presentation in tumor cells independent of IFN (Such <i>et al.</i> (2020) J Clin Invest, doi: 10.1172/JCI131572). We demonstrated that tumor cell-intrinsic activation of the cytosolic innate immunoreceptor RIG-I by its synthetic ligand 3pRNA overcomes transcriptional HLA-I APM suppression in patient-derived IFN-resistant melanoma cells. <i>De novo</i> HLA-I APM expression is IRF1/IRF3-dependent and re-sensitizes melanoma cells to autologous cytotoxic CD8+ T cells. Notably, synthetic RIG-I ligands and ICB synergize in T cell activation, suggesting combinational therapy could be an efficient strategy to improve patient outcomes in melanoma.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2021-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25342854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}