Cell Stress最新文献

{"title":"Genotoxic stress signalling as a driver of macrophage diversity.","authors":"Ana Kasapi,&nbsp;Antigoni Triantafyllopoulou","doi":"10.15698/cst2022.03.265","DOIUrl":"https://doi.org/10.15698/cst2022.03.265","url":null,"abstract":"<p><p>Tissue macrophages arise from yolk sac, fetal liver and hematopoietic progenitors and adopt diverse transcriptional programs and phenotypes, instructed by their microenvironment. In chronic inflammation, such as in chronic infections, autoimmunity, or cancer, tissue microenvironments change dramatically thus imprinting new programs on tissue macrophages. While stress is a known driver of carcinogenesis in epithelial cells, emerging evidence suggests that macrophage responses to genotoxic stress are embedded in their 'physiologic' immune and tissue healing programs and in most cases do not lead to myeloid malignancies. The role of genotoxic stress as an instructor of macrophage-mediated immune defense and tissue remodeling is only beginning to be understood. Here, we review the evidence showing that genotoxic stress, which macrophages and their precursors face upon encountering inflammatory and/or growth signals, instructs their transcriptional programs, by activating non-canonical, cell-type specific DNA Damage Response (DDR)-driven signaling pathways. We propose that immune-cell specific, DDR-instructed programs are crucial for tissue homeostasis as well as for the maintenance and resolution of inflammatory responses in infection, cancer, autoinflammatory and autoimmune microenvironments.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"6 3","pages":"30-44"},"PeriodicalIF":6.4,"publicationDate":"2022-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8892193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40322270","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":"MYCN upregulates the transsulfuration pathway to suppress the ferroptotic vulnerability in <i>MYCN</i>-amplified neuroblastoma.","authors":"Konstantinos V Floros, Ayesha T Chawla, Mia O Johnson-Berro, Rishabh Khatri, Angeliki M Stamatouli, Sosipatros A Boikos, Mikhail G Dozmorov, L Ashley Cowart, Anthony C Faber","doi":"10.15698/cst2022.02.264","DOIUrl":"10.15698/cst2022.02.264","url":null,"abstract":"<p><p>Ferroptosis is an iron-dependent, oxidative form of cell death that is countered mainly by glutathione peroxidase 4 (GPX4) and the production of glutathione (GSH), which is formed from cysteine. The identification of the cancers that may benefit from pharmacological ferroptotic induction is just emerging. We recently demonstrated that inducing ferroptosis genetically or pharmacologically in <i>MYCN</i>-amplified neuroblastoma (NB) is a novel and effective way to kill these cells. MYCN increases iron metabolism and subsequent hydroxyl radicals through increased expression of the transferrin receptor 1 (TfR1) and low levels of the ferroportin receptor. To counter increased hydroxyl radicals, MYCN binds to the promoter of <i>SLC3A2</i> (solute carrier family 3 member 2). SLC3A2 is a subunit of system Xc-, which is the cysteine-glutamate antiporter that exports glutamate and imports cystine. Cystine is converted to cysteine intracellularly. Here, we investigated other ways MYCN may increase cysteine levels. By performing metabolomics in a syngeneic NB cell line either expressing MYCN or GFP, we demonstrate that the transsulfuration pathway is activated by MYCN. Furthermore, we demonstrate that <i>MYCN</i>-amplified NB cell lines and tumors have higher levels of cystathionine beta-synthase (CBS), the rate-limiting enzyme in transsulfuration, which leads to higher levels of the thioether cystathionine (<i>R-S</i>-(2-amino-2-carboxyethyl)-l-homocysteine). In addition, <i>MYCN</i>-amplified NB tumors have high levels of methylthioadenosine phosphorylase (MTAP), an enzyme that helps salvage methionine following polyamine metabolism. MYCN directly binds to the promoter of <i>MTAP</i>. We propose that MYCN orchestrates both enhanced cystine uptake and enhanced activity of the transsulfuration pathway to counteract increased reactive oxygen species (ROS) from iron-induced Fenton reactions, ultimately contributing to a ferroptosis vulnerability in <i>MYCN</i>-amplified neuroblastoma.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"6 2","pages":"21-29"},"PeriodicalIF":4.1,"publicationDate":"2022-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8802432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39792363","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":"Building and breaking the gut barrier with bariatric surgery.","authors":"Mohammed K Hankir","doi":"10.15698/cst2022.02.263","DOIUrl":"https://doi.org/10.15698/cst2022.02.263","url":null,"abstract":"<p><p>Bariatric surgery has been proposed to improve glycemic control in morbidly obese patients by stabilising the gut barrier and alleviating endotoxemia-induced insulin resistance. Here, recent studies are highlighted which reveal site-specific and at times opposing effects of bariatric surgery on the gut barrier. Further understanding the underlying mechanisms may not only inform the development of novel gut-based drugs for the initial treatment of type 2 diabetes, but possibly also assist in the management of its eventual relapse.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"6 2","pages":"17-20"},"PeriodicalIF":6.4,"publicationDate":"2021-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8802433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39792362","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":"Evaluation of I-TAC as a potential early plasma marker to differentiate between critical and non-critical COVID-19.","authors":"Yushan Zhang, Chao Xu, Nelson I Agudelo Higuita, Resham Bhattacharya, Jennifer Holter Chakrabarty, Priyabrata Mukherjee","doi":"10.15698/cst2022.01.262","DOIUrl":"10.15698/cst2022.01.262","url":null,"abstract":"<p><p>The COVID-19 pandemic has led to significant global health and economic consequences. There is an unmet need to define a molecular fingerprint of severity of the disease that may guide an early, rational and directed intervention preventing severe illness. We collected plasma from patients with moderate (nine cases), severe (22 cases) and critical (five cases) COVID-19 within three days of hospitalization (approximately one week after symptom onset) and used a cytokine antibody array to screen the 105 cytokines included in the array. We found that I-TAC, IP-10, ST2 and IL-1ra were significantly upregulated in patients with critical disease as compared to the non-critical (moderate and severe combined). ELISA further quantified I-TAC levels as 590.24±410.89, 645.35±517.59 and 1613.53±1010.59 pg/ml in moderate, severe and critical groups, respectively. Statistical analysis showed that I-TAC levels were significantly higher in patients with critical disease when compared with moderate (p = 0.04), severe (p = 0.03) or the combined non-critical (p = 0.02) group. Although limited by the low sample numbers, this study may suggest a role of I-TAC as a potential early marker to discriminate between critical and non-critical COVID-19 cases. Such knowledge is urgently needed for appropriate allocation of resources and to serve as a platform for future research towards early interventions that could mitigate disease severity and save lives.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"6 1","pages":"6-16"},"PeriodicalIF":6.4,"publicationDate":"2021-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10671009","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":"p38 regulates the tumor suppressor PDCD4 via the TSC-mTORC1 pathway.","authors":"Clarissa Braun, Karl Katholnig, Christopher Kaltenecker, Monika Linke, Nyamdelger Sukhbaatar, Markus Hengstschläger, Thomas Weichhart","doi":"10.15698/cst2021.12.260","DOIUrl":"10.15698/cst2021.12.260","url":null,"abstract":"<p><p>Programmed cell death protein 4 (PDCD4) exerts critical functions as tumor suppressor and in immune cells to regulate inflammatory processes. The phosphoinositide 3-kinase (PI3K) promotes degradation of PDCD4 via mammalian target of rapamycin complex 1 (mTORC1). However, additional pathways that may regulate PDCD4 expression are largely ill-defined. In this study, we have found that activation of the mitogen-activated protein kinase p38 promoted degradation of PDCD4 in macrophages and fibroblasts. Mechanistically, we identified a pathway from p38 and its substrate MAP kinase-activated protein kinase 2 (MK2) to the tuberous sclerosis complex (TSC) to regulate mTORC1-dependent degradation of PDCD4. Moreover, we provide evidence that TSC1 and TSC2 regulate PDCD4 expression via an additional mechanism independent of mTORC1. These novel data extend our knowledge of how PDCD4 expression is regulated by stress- and nutrient-sensing pathways.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"5 12","pages":"176-182"},"PeriodicalIF":6.4,"publicationDate":"2021-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9401128","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":"Mechanisms of YAP/TAZ transcriptional control.","authors":"Giusy Battilana,&nbsp;Francesca Zanconato,&nbsp;Stefano Piccolo","doi":"10.15698/cst2021.11.258","DOIUrl":"https://doi.org/10.15698/cst2021.11.258","url":null,"abstract":"<p><p>Dysregulated gene expression is intrinsic to cell transformation, tumorigenesis and metastasis. Cancer-specific gene-expression profiles stem from gene regulatory networks fueled by genetic and epigenetic defects, and by abnormal signals of the tumor microenvironment. These oncogenic signals ultimately engage the transcriptional machinery on the cis -regulatory elements of a host of effector genes, through recruitment of transcription factors (TFs), co-activators and chromatin regulators. That said, whether gene-expression in cancer cells is the chaotic product of myriad regulations or rather a relatively ordered process orchestrated by few TFs (master regulators) has long remained enigmatic. Recent work on the YAP/TAZ co-activators has been instrumental to break new ground into this outstanding issue, revealing that tumor cells hijack growth programs that are active during development and regeneration through engagement of a small set of interconnected TFs and their nuclear partners.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"5 11","pages":"167-172"},"PeriodicalIF":6.4,"publicationDate":"2021-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39716694","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":"GRASPing the unconventional secretory machinery to bridge cellular stress signaling to the extracellular proteome.","authors":"Constantinos Demetriades,&nbsp;Julian Nüchel,&nbsp;Markus Plomann","doi":"10.15698/cst2021.11.259","DOIUrl":"https://doi.org/10.15698/cst2021.11.259","url":null,"abstract":"<p><p>Cellular adaptation to stress is a crucial homeostatic process for survival, metabolism, physiology, and disease. Cells respond to stress stimuli (e.g., nutrient starvation, growth factor deprivation, hypoxia, low energy, etc.) by changing the activity of signaling pathways, and interact with their environment by qualitatively and quantitatively modifying their intracellular, surface, and extracellular proteomes. How this delicate communication takes place is a hot topic in cell biological research, and has important implications for human disease.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"5 11","pages":"173-175"},"PeriodicalIF":6.4,"publicationDate":"2021-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8561302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39716693","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":"Macroautophagy and normal aging of the nervous system: Lessons from animal models.","authors":"Emmanouela Kallergi,&nbsp;Vassiliki Nikoletopoulou","doi":"10.15698/cst2021.10.257","DOIUrl":"https://doi.org/10.15698/cst2021.10.257","url":null,"abstract":"<p><p>Aging represents a cumulative form of cellular stress, which is thought to challenge many aspects of proteostasis. The non-dividing, long-lived neurons are particularly vulnerable to stress, and, not surprisingly, even normal aging is highly associated with a decline in brain function in humans, as well as in other animals. Macroautophagy is a fundamental arm of the proteostasis network, safeguarding proper protein turnover during different cellular states and against diverse cellular stressors. An intricate interplay between macroautophagy and aging is beginning to unravel, with the emergence of new tools, including those for monitoring autophagy in cultured neurons and in the nervous system of different organisms <i>in vivo</i>. Here, we review recent findings on the impact of aging on neuronal integrity and on neuronal macroautophagy, as they emerge from studies in invertebrate and mammalian models.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"5 10","pages":"146-166"},"PeriodicalIF":6.4,"publicationDate":"2021-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39567324","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":"Host upregulation of lipid droplets drives antiviral responses.","authors":"Ebony A Monson,&nbsp;Karla J Helbig","doi":"10.15698/cst2021.09.256","DOIUrl":"https://doi.org/10.15698/cst2021.09.256","url":null,"abstract":"<p><p>When a host cell is infected by a virus, it activates the innate immune response, setting off a cascade of signalling events leading to the production of an antiviral response. This immune response is typically robust and in general works well to clear viral infections, however, viruses have evolved evasion strategies to combat this, and therefore, a better understanding of how this response works in more detail is needed for the development of novel and effective therapeutics. Lipid droplets (LDs) are intracellular organelles and have historically been thought of simply as cellular energy sources, however, have more recently been recognised as critical organelles in signalling events. Importantly, many viruses are known to take over host cellular production of LDs, and it has traditionally been assumed the sole purpose of this is to supply energy for viral life cycle events. However, our recent work positions LDs as important organelles during the first few hours of an antiviral response, showing that they underpin the production of important antiviral cytokines following viral infection. Following infection of cells with either RNA viruses (Zika, Dengue, Influenza A) or a DNA (Herpes Simplex Virus-1) virus, LDs were rapidly upregulated, and this response was also replicated following stimulation with viral mimic agonists. This upregulation of LDs following infection was transient, and interestingly, did not follow the well described homeostatic mechanism of LD upregulation, instead being controlled by EGFR. The cell's ability to mount an effective immune response was greatly diminished when inhibiting EGFR, thus inhibiting LD upregulation during infection, also leading to an increase in viral replication. In this microreview, we extrapolate our recent findings and discuss LDs as an important organelle in the innate immune response.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"5 9","pages":"143-145"},"PeriodicalIF":6.4,"publicationDate":"2021-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39420927","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":"Atg8ylation as a general membrane stress and remodeling response.","authors":"Suresh Kumar, Jingyue Jia, Vojo Deretic","doi":"10.15698/cst2021.09.255","DOIUrl":"10.15698/cst2021.09.255","url":null,"abstract":"<p><p>The yeast Atg8 protein and its paralogs in mammals, mammalian Atg8s (mAtg8s), have been primarily appreciated for their participation in autophagy. However, lipidated mAtg8s, including the most frequently used autophagosomal membrane marker LC3B, are found on cellular membranes other than autophagosomes. Here we put forward a hypothesis that the lipidation of mAtg8s, termed 'Atg8ylation', is a general membrane stress and remodeling response analogous to the role that ubiquitylation plays in tagging proteins. Ubiquitin and mAtg8s are related in sequence and structure, and the lipidation of mAtg8s occurs on its C-terminal glycine, akin to the C-terminal glycine of ubiquitin. Conceptually, we propose that mAtg8s and Atg8ylation are to membranes what ubiquitin and ubiquitylation are to proteins, and that, like ubiquitylation, Atg8ylation has a multitude of downstream effector outputs, one of which is autophagy.</p>","PeriodicalId":36371,"journal":{"name":"Cell Stress","volume":"5 9","pages":"128-142"},"PeriodicalIF":6.4,"publicationDate":"2021-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39420928","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}