PLoS Biology最新文献

{"title":"RIPK1 is required for ZBP1-driven necroptosis in human cells.","authors":"Oluwamuyiwa T Amusan, Shuqi Wang, Chaoran Yin, Heather S Koehler, Yixun Li, Tencho Tenev, Rebecca Wilson, Benjamin Bellenie, Ting Zhang, Jian Wang, Chang Liu, Kim Seong, Seyedeh L Poorbaghi, Joseph Yates, Yuchen Shen, Jason W Upton, Pascal Meier, Siddharth Balachandran, Hongyan Guo","doi":"10.1371/journal.pbio.3002845","DOIUrl":"https://doi.org/10.1371/journal.pbio.3002845","url":null,"abstract":"<p><p>Necroptosis initiated by the host sensor Z-NA binding protein 1 (ZBP1) is essential for host defense against a growing number of viruses, including herpes simplex virus 1 (HSV-1). Studies with HSV-1 and other necroptogenic stimuli in murine settings have suggested that ZBP1 triggers necroptosis by directly complexing with the kinase RIPK3. Whether this is also the case in human cells, or whether additional co-factors are needed for ZBP1-mediated necroptosis, is unclear. Here, we show that ZBP1-induced necroptosis in human cells requires RIPK1. We have found that RIPK1 is essential for forming a stable and functional ZBP1-RIPK3 complex in human cells, but is dispensable for the formation of the equivalent murine complex. The receptor-interacting protein (RIP) homology interaction motif (RHIM) in RIPK3 is responsible for this difference between the 2 species, because replacing the RHIM in human RIPK3 with the RHIM from murine RIPK3 is sufficient to overcome the requirement for RIPK1 in human cells. These observations describe a critical mechanistic difference between mice and humans in how ZBP1 engages in necroptosis, with important implications for treating human diseases.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3002845"},"PeriodicalIF":9.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Caspase 3 and caspase 7 promote cytoprotective autophagy and the DNA damage response during non-lethal stress conditions in human breast cancer cells.","authors":"Gayathri Samarasekera, Nancy E Go, Courtney Choutka, Jing Xu, Yuka Takemon, Jennifer Chan, Michelle Chan, Shivani Perera, Samuel Aparicio, Gregg B Morin, Marco A Marra, Suganthi Chittaranjan, Sharon M Gorski","doi":"10.1371/journal.pbio.3003034","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003034","url":null,"abstract":"<p><p>Cell stress adaptation plays a key role in normal development and in various diseases including cancer. Caspases are activated in response to cell stress, and growing evidence supports their function in non-apoptotic cellular processes. A role for effector caspases in promoting stress-induced cytoprotective autophagy was demonstrated in Drosophila, but has not been explored in the context of human cells. We found a functionally conserved role for effector caspase 3 (CASP3) and caspase 7 (CASP7) in promoting starvation or proteasome inhibition-induced cytoprotective autophagy in human breast cancer cells. The loss of CASP3 and CASP7 resulted in an increase in PARP1 cleavage, reduction in LC3B and ATG7 transcript levels, and a reduction in H2AX phosphorylation, consistent with a block in autophagy and DNA damage-induced stress response pathways. Surprisingly, in non-lethal cell stress conditions, CASP7 underwent non-canonical processing at two calpain cleavage sites flanking a PARP1 exosite, resulting in stable CASP7-p29/p30 fragments. Expression of CASP7-p29/p30 fragment(s) could rescue H2AX phosphorylation in the CASP3 and CASP7 double knockout background. Strikingly, yet consistent with these phenotypes, the loss of CASP3 and CASP7 exhibited synthetic lethality with BRCA1 loss. These findings support a role for human caspases in stress adaptation through PARP1 modulation and reveal new therapeutic avenues for investigation.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003034"},"PeriodicalIF":9.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage invasion into the Drosophila brain requires JAK/STAT-dependent MMP activation in the blood-brain barrier.","authors":"Bente Winkler, Dominik Funke, Christian Klämbt","doi":"10.1371/journal.pbio.3003035","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003035","url":null,"abstract":"<p><p>The central nervous system is well-separated from external influences by the blood-brain barrier. Upon surveillance, infection or neuroinflammation; however, peripheral immune cells can enter the brain where they often cause detrimental effects. To invade the brain, immune cells not only have to breach cellular barriers, but they also need to traverse associated extracellular matrix barriers. Neither in vertebrates nor in invertebrates is it fully understood how these processes are molecularly controlled. We recently established Drosophila melanogaster as a model to elucidate peripheral immune cell invasion into the brain. Here, we show that neuroinflammation leads to the expression of Unpaired cytokines that activate the JAK/STAT signaling pathway in glial cells of the blood-brain barrier. This in turn triggers the expression of matrix metalloproteinases enabling remodeling of the extracellular matrix enclosing the fly brain and a subsequent invasion of immune cells into the brain. Our study demonstrates conserved mechanisms underlying immune cell invasion of the nervous system in invertebrates and vertebrates and could, thus, further contribute to understanding of JAK/STAT signaling during neuroinflammation.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003035"},"PeriodicalIF":9.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143469685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural development goes retro: Gags as essential modulators of synapse formation.","authors":"Yung-Heng Chang, Josh Dubnau","doi":"10.1371/journal.pbio.3003032","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003032","url":null,"abstract":"<p><p>Neurodevelopment requires dynamic control of synapse number. A new study in PLOS Biology reveals that the gag protein of Copia, an active retrotransposon, forms virus-like capsids that transfer its own RNA across the Drosophila neuromuscular junction. Here, Copia acts antagonistically with Arc, another retrotransposon gag protein, to regulate synapse formation.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003032"},"PeriodicalIF":9.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Capsid transfer of the retrotransposon Copia controls structural synaptic plasticity in Drosophila.","authors":"P Githure M'Angale, Adrienne Lemieux, Yumeng Liu, Shuhao Wang, Max Zinter, Gimena Alegre, Alfred Simkin, Vivian Budnik, Brian A Kelch, Travis Thomson","doi":"10.1371/journal.pbio.3002983","DOIUrl":"10.1371/journal.pbio.3002983","url":null,"abstract":"<p><p>Transposons are parasitic genome elements that can also serve as raw material for the evolution of new cellular functions. However, how retrotransposons are selected and domesticated by host organisms to modulate synaptic plasticity remains largely unknown. Here, we show that the Ty1 retrotransposon Copia forms virus-like capsids in vivo and transfers between cells. Copia is enriched at the Drosophila neuromuscular junction (NMJ) and transported across synapses, and disrupting its expression promotes both synapse development and structural synaptic plasticity. We show that proper synaptic plasticity is maintained in Drosophila by the balance of Copia and the Arc1 (activity-regulated cytoskeleton-associated protein) homolog. High-resolution cryogenic-electron microscopy imaging shows that the structure of the Copia capsid has a large capacity and pores like retroviruses but is distinct from domesticated capsids such as dArc1. Our results suggest a fully functional transposon mediates synaptic plasticity, possibly representing an early stage of domestication of a retrotransposon.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3002983"},"PeriodicalIF":9.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835246/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson's disease.","authors":"Lijun Dai, Jiannan Wang, Lanxia Meng, Xingyu Zhang, Tingting Xiao, Min Deng, Guiqin Chen, Jing Xiong, Wei Ke, Zhengyuan Hong, Lihong Bu, Zhentao Zhang","doi":"10.1371/journal.pbio.3002974","DOIUrl":"10.1371/journal.pbio.3002974","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies α-Syn pathology, whereas genetic removal of CYP46A1 attenuates α-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by α-Syn fibrils. Intracerebral injection of 24-OHC enhances the spread of α-Syn pathology and dopaminergic neurodegeneration via elevated X-box binding protein 1 (XBP1) and lymphocyte-activation gene 3 (LAG3) levels. Thus, elevated CYP46A1 and 24-OHC promote neurotoxicity and the spread of α-Syn via the XBP1-LAG3 axis. Strategies aimed at inhibiting the CYP46A1-24-OHC axis and LAG3 could hold promise as disease-modifying therapies for PD.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3002974"},"PeriodicalIF":9.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gap junctions allow transfer of metabolites between germ cells and somatic cells to promote germ cell growth in the Drosophila ovary.","authors":"Caroline Vachias, Camille Tourlonias, Louis Grelée, Nathalie Gueguen, Yoan Renaud, Parvathy Venugopal, Graziella Richard, Pierre Pouchin, Emilie Brasset, Vincent Mirouse","doi":"10.1371/journal.pbio.3003045","DOIUrl":"https://doi.org/10.1371/journal.pbio.3003045","url":null,"abstract":"<p><p>Gap junctions allow the exchange of small molecules between cells. How this function could be used to promote cell growth is not yet fully understood. During Drosophila ovarian follicle development, germ cells, which are surrounded by epithelial somatic cells, undergo massive growth. We found that this growth depends on gap junctions between these cell populations, with a requirement for Innexin4 and Innexin2, in the germ cells and the somatic cells, respectively. Translatomic analyses revealed that somatic cells express enzymes and transporters involved in amino acid metabolism that are absent in germ cells. Among them, we identified a putative amino acid transporter required for germline growth. Its ectopic expression in the germline can partially compensate for its absence or the one of Innexin2 in somatic cells. Moreover, affecting either gap junctions or the import of some amino acids in somatic cells induces P-bodies in the germ cells, a feature usually associated with an arrest of translation. Finally, in somatic cells, innexin2 expression and gap junction assembly are regulated by the insulin receptor/PI3K kinase pathway, linking the growth of the two tissues. Overall, these results support the view that metabolic transfer through gap junction promotes cell growth and illustrate how such a mechanism can be integrated into a developmental program, coupling growth control by extrinsic systemic signals with the intrinsic coordination between cell populations.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003045"},"PeriodicalIF":9.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GitHub enables collaborative and reproducible laboratory research.","authors":"Katharine Y Chen, Maria Toro-Moreno, Arvind Rasi Subramaniam","doi":"10.1371/journal.pbio.3003029","DOIUrl":"10.1371/journal.pbio.3003029","url":null,"abstract":"<p><p>GitHub, a platform widely used in software development, offers a robust framework for documenting all activities of laboratory research projects. This Community Page highlights the benefits of, and provides guidance for, incorporating the GitHub ecosystem into \"wet\" lab workflows.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003029"},"PeriodicalIF":9.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11828340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toll-1-dependent immune evasion induced by fungal infection leads to cell loss in the Drosophila brain.","authors":"Deepanshu N D Singh, Abigail R E Roberts, Xiaocui Wang, Guiyi Li, Enrique Quesada Moraga, David Alliband, Elizabeth Ballou, Hung-Ji Tsai, Alicia Hidalgo","doi":"10.1371/journal.pbio.3003020","DOIUrl":"10.1371/journal.pbio.3003020","url":null,"abstract":"<p><p>Fungi can intervene in hosts' brain function. In humans, they can drive neuroinflammation, neurodegenerative diseases and psychiatric disorders. However, how fungi alter the host brain is unknown. The mechanism underlying innate immunity to fungi is well-known and universally conserved downstream of shared Toll/TLR receptors, which via the adaptor MyD88 and the transcription factor Dif/NFκB, induce the expression of antimicrobial peptides (AMPs). However, in the brain, Toll-1 could also drive an alternative pathway via Sarm, which causes cell death instead. Sarm is the universal inhibitor of MyD88 and could drive immune evasion. Here, we show that exposure to the fungus Beauveria bassiana reduced fly life span, impaired locomotion and caused neurodegeneration. Beauveria bassiana entered the Drosophila brain and induced the up-regulation of AMPs, and the Toll adaptors wek and sarm, within the brain. RNAi knockdown of Toll-1, wek or sarm concomitantly with infection prevented B. bassiana-induced cell loss. By contrast, over-expression of wek or sarm was sufficient to cause neuronal loss in the absence of infection. Thus, B. bassiana caused cell loss in the host brain via Toll-1/Wek/Sarm signalling driving immune evasion. A similar activation of Sarm downstream of TLRs upon fungal infections could underlie psychiatric and neurodegenerative diseases in humans.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3003020"},"PeriodicalIF":9.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Landscape-level human disturbance results in loss and contraction of mammalian populations in tropical forests.","authors":"Ilaria Greco, Lydia Beaudrot, Chris Sutherland, Simone Tenan, Chia Hsieh, Daniel Gorczynski, Douglas Sheil, Jedediah Brodie, Mohammad Firoz Ahmed, Jorge Ahumada, Rajan Amin, Megan Baker-Watton, Ramie Husneara Begum, Francesco Bisi, Robert Bitariho, Ahimsa Campos-Arceiz, Elildo A R Carvalho, Daniel Cornélis, Giacomo Cremonesi, Virgínia Londe de Camargos, Iariaella Elimanantsoa, Santiago Espinosa, Adeline Fayolle, Davy Fonteyn, Abishek Harihar, Harry Hilser, Alys Granados, Patrick A Jansen, Jayasilan Mohd-Azlan, Caspian Johnson, Steig Johnson, Dipankar Lahkar, Marcela Guimarães Moreira Lima, Matthew Scott Luskin, Marcelo Magioli, Emanuel H Martin, Adriano Martinoli, Ronaldo Gonçalves Morato, Badru Mugerwa, Lain E Pardo, Julia Salvador, Fernanda Santos, Cédric Vermeulen, Patricia C Wright, Francesco Rovero","doi":"10.1371/journal.pbio.3002976","DOIUrl":"10.1371/journal.pbio.3002976","url":null,"abstract":"<p><p>Tropical forests hold most of Earth's biodiversity and a higher concentration of threatened mammals than other biomes. As a result, some mammal species persist almost exclusively in protected areas, often within extensively transformed and heavily populated landscapes. Other species depend on remaining remote forested areas with sparse human populations. However, it remains unclear how mammalian communities in tropical forests respond to anthropogenic pressures in the broader landscape in which they are embedded. As governments commit to increasing the extent of global protected areas to prevent further biodiversity loss, identifying the landscape-level conditions supporting wildlife has become essential. Here, we assessed the relationship between mammal communities and anthropogenic threats in the broader landscape. We simultaneously modeled species richness and community occupancy as complementary metrics of community structure, using a state-of-the-art community model parameterized with a standardized pan-tropical data set of 239 mammal species from 37 forests across 3 continents. Forest loss and fragmentation within a 50-km buffer were associated with reduced occupancy in monitored communities, while species richness was unaffected by them. In contrast, landscape-scale human density was associated with reduced mammal richness but not occupancy, suggesting that sensitive species have been extirpated, while remaining taxa are relatively unaffected. Taken together, these results provide evidence of extinction filtering within tropical forests triggered by anthropogenic pressure occurring in the broader landscape. Therefore, existing and new reserves may not achieve the desired biodiversity outcomes without concurrent investment in addressing landscape-scale threats.</p>","PeriodicalId":49001,"journal":{"name":"PLoS Biology","volume":"23 2","pages":"e3002976"},"PeriodicalIF":9.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}