Michael Schmitz, Irma Querques, Seraina Oberli, Christelle Chanez, Martin Jinek
CRISPR-Cas systems have been co-opted by Tn7-like transposable elements to direct RNA-guided transposition. Type V-K CRISPR-associated transposons rely on the concerted activities of the pseudonuclease Cas12k, the AAA+ ATPase TnsC, the Zn-finger protein TniQ, and the transposase TnsB. Here we present a cryo-electron microscopic structure of a target DNA-bound Cas12k-transposon recruitment complex comprised of RNA-guided Cas12k, TniQ, a polymeric TnsC filament and, unexpectedly, the ribosomal protein S15. Complex assembly, mediated by a network of interactions involving the guide RNA, TniQ, and S15, results in R-loop completion...
November 23, 2022: Cell
Xia Yao, Shuai Gao, Jixin Wang, Zhangqiang Li, Jian Huang, Yan Wang, Zhifei Wang, Jiaofeng Chen, Xiao Fan, Weipeng Wang, Xueqin Jin, Xiaojing Pan, Yong Yu, Armando Lagrutta, Nieng Yan
Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate the inhibition of cardiomyocyte calcium handling by amiodarone, which functions as a multi-channel antagonist, and implicate its inhibitory effect on L-type Cav channels, but the molecular mechanism has remained unclear. Here we present systematic cryo-EM structural analysis of Cav 1.1 and Cav 1.3 treated with amiodarone or sofosbuvir alone, or sofosbuvir/MNI-1 combined with amiodarone...
November 17, 2022: Cell
Zeyu Jin, Li Wan, Yuqi Zhang, Xuecheng Li, Yong Cao, Haobin Liu, Shengyao Fan, Du Cao, Zhengmao Wang, Xiaobo Li, Junmin Pan, Meng-Qiu Dong, Jianping Wu, Zhen Yan
The TOC and TIC complexes are essential translocons that facilitate the import of the nuclear genome-encoded preproteins across the two envelope membranes of chloroplast, but their exact molecular identities and assembly remain unclear. Here, we report a cryoelectron microscopy structure of TOC-TIC supercomplex from Chlamydomonas, containing a total of 14 identified components. The preprotein-conducting pore of TOC is a hybrid β-barrel co-assembled by Toc120 and Toc75, while the potential translocation path of TIC is formed by transmembrane helices from Tic20 and YlmG, rather than a classic model of Tic110...
November 15, 2022: Cell
Tulika Singh, Kwan-Ki Hwang, Andrew S Miller, Rebecca L Jones, Cesar A Lopez, Sarah J Dulson, Camila Giuberti, Morgan A Gladden, Itzayana Miller, Helen S Webster, Joshua A Eudailey, Kan Luo, Tarra Von Holle, Robert J Edwards, Sarah Valencia, Katherine E Burgomaster, Summer Zhang, Jesse F Mangold, Joshua J Tu, Maria Dennis, S Munir Alam, Lakshmanane Premkumar, Reynaldo Dietze, Theodore C Pierson, Eng Eong Ooi, Helen M Lazear, Richard J Kuhn, Sallie R Permar, Mattia Bonsignori
Congenital Zika virus (ZIKV) infection results in neurodevelopmental deficits in up to 14% of infants born to ZIKV-infected mothers. Neutralizing antibodies are a critical component of protective immunity. Here, we demonstrate that plasma IgM contributes to ZIKV immunity in pregnancy, mediating neutralization up to 3 months post-symptoms. From a ZIKV-infected pregnant woman, we isolated a pentameric ZIKV-specific IgM (DH1017.IgM) that exhibited ultrapotent ZIKV neutralization dependent on the IgM isotype...
November 14, 2022: Cell
Cyril Le Nouën, Christine E Nelson, Xueqiao Liu, Hong-Su Park, Yumiko Matsuoka, Cindy Luongo, Celia Santos, Lijuan Yang, Richard Herbert, Ashley Castens, Ian N Moore, Temeri Wilder-Kofie, Rashida Moore, April Walker, Peng Zhang, Paolo Lusso, Reed F Johnson, Nicole L Garza, Laura E Via, Shirin Munir, Daniel L Barber, Ursula J Buchholz
Pediatric SARS-CoV-2 vaccines are needed that elicit immunity directly in the airways as well as systemically. Building on pediatric parainfluenza virus vaccines in clinical development, we generated a live-attenuated parainfluenza-virus-vectored vaccine candidate expressing SARS-CoV-2 prefusion-stabilized spike (S) protein (B/HPIV3/S-6P) and evaluated its immunogenicity and protective efficacy in rhesus macaques. A single intranasal/intratracheal dose of B/HPIV3/S-6P induced strong S-specific airway mucosal immunoglobulin A (IgA) and IgG responses...
November 10, 2022: Cell
John Janetzko, Ryoji Kise, Benjamin Barsi-Rhyne, Dirk H Siepe, Franziska M Heydenreich, Kouki Kawakami, Matthieu Masureel, Shoji Maeda, K Christopher Garcia, Mark von Zastrow, Asuka Inoue, Brian K Kobilka
Binding of arrestin to phosphorylated G protein-coupled receptors (GPCRs) is crucial for modulating signaling. Once internalized, some GPCRs remain complexed with β-arrestins, while others interact only transiently; this difference affects GPCR signaling and recycling. Cell-based and in vitro biophysical assays reveal the role of membrane phosphoinositides (PIPs) in β-arrestin recruitment and GPCR-β-arrestin complex dynamics. We find that GPCRs broadly stratify into two groups, one that requires PIP binding for β-arrestin recruitment and one that does not...
November 8, 2022: Cell
Xiaonan Fu, Li Sun, Runze Dong, Jane Y Chen, Runglawan Silakit, Logan F Condon, Yiing Lin, Shin Lin, Richard D Palmiter, Liangcai Gu
Methods for acquiring spatially resolved omics data from complex tissues use barcoded DNA arrays of low- to sub-micrometer features to achieve single-cell resolution. However, fabricating such arrays (randomly assembled beads, DNA nanoballs, or clusters) requires sequencing barcodes in each array, limiting cost-effectiveness and throughput. Here, we describe a vastly scalable stamping method to fabricate polony gels, arrays of ∼1-micrometer clonal DNA clusters bearing unique barcodes. By enabling repeatable enzymatic replication of barcode-patterned gels, this method, compared with the sequencing-dependent array fabrication, reduced cost by at least 35-fold and time to approximately 7 h...
November 4, 2022: Cell
Joseph W Saelens, Mollie I Sweeney, Gopinath Viswanathan, Ana María Xet-Mull, Kristen L Jurcic Smith, Dana M Sisk, Daniel D Hu, Rachel M Cronin, Erika J Hughes, W Jared Brewer, Jörn Coers, Matthew M Champion, Patricia A Champion, Craig B Lowe, Clare M Smith, Sunhee Lee, Jason E Stout, David M Tobin
The human pathogen Mycobacterium tuberculosis typically causes lung disease but can also disseminate to other tissues. We identified a M. tuberculosis (Mtb) outbreak presenting with unusually high rates of extrapulmonary dissemination and bone disease. We found that the causal strain carried an ancestral full-length version of the type VII-secreted effector EsxM rather than the truncated version present in other modern Mtb lineages. The ancestral EsxM variant exacerbated dissemination through enhancement of macrophage motility, increased egress of macrophages from established granulomas, and alterations in macrophage actin dynamics...
November 4, 2022: Cell
Daniel G Dumitrescu, Elizabeth M Gordon, Yekaterina Kovalyova, Anna B Seminara, Brianna Duncan-Lowey, Emily R Forster, Wen Zhou, Carmen J Booth, Aimee Shen, Philip J Kranzusch, Stavroula K Hatzios
Low-molecular-weight (LMW) thiols are small-molecule antioxidants required for the maintenance of intracellular redox homeostasis. However, many host-associated microbes, including the gastric pathogen Helicobacter pylori, unexpectedly lack LMW-thiol biosynthetic pathways. Using reactivity-guided metabolomics, we identified the unusual LMW thiol ergothioneine (EGT) in H. pylori. Dietary EGT accumulates to millimolar levels in human tissues and has been broadly implicated in mitigating disease risk. Although certain microorganisms synthesize EGT, we discovered that H...
November 3, 2022: Cell
Luke Funk, Kuan-Chung Su, Jimmy Ly, David Feldman, Avtar Singh, Brittania Moodie, Paul C Blainey, Iain M Cheeseman
Understanding the basis for cellular growth, proliferation, and function requires determining the roles of essential genes in diverse cellular processes, including visualizing their contributions to cellular organization and morphology. Here, we combined pooled CRISPR-Cas9-based functional screening of 5,072 fitness-conferring genes in human HeLa cells with microscopy-based imaging of DNA, the DNA damage response, actin, and microtubules. Analysis of >31 million individual cells identified measurable phenotypes for >90% of gene knockouts, implicating gene targets in specific cellular processes...
November 2, 2022: Cell
Jinfan Wang, Byung-Sik Shin, Carlos Alvarado, Joo-Ran Kim, Jonathan Bohlen, Thomas E Dever, Joseph D Puglisi
How the eukaryotic 43S preinitiation complex scans along the 5' untranslated region (5' UTR) of a capped mRNA to locate the correct start codon remains elusive. Here, we directly track yeast 43S-mRNA binding, scanning, and 60S subunit joining by real-time single-molecule fluorescence spectroscopy. 43S engagement with mRNA occurs through a slow, ATP-dependent process driven by multiple initiation factors including the helicase eIF4A. Once engaged, 43S scanning occurs rapidly and directionally at ∼100 nucleotides per second, independent of multiple cycles of ATP hydrolysis by RNA helicases post ribosomal loading...
November 2, 2022: Cell
Haopeng Xiao, Luiz H M Bozi, Yizhi Sun, Christopher L Riley, Vivek M Philip, Mandy Chen, Jiaming Li, Tian Zhang, Evanna L Mills, Margo P Emont, Wenfei Sun, Anita Reddy, Ryan Garrity, Jiani Long, Tobias Becher, Laura Potano Vitas, Dina Laznik-Bogoslavski, Martha Ordonez, Xinyue Liu, Xiong Chen, Yun Wang, Weihai Liu, Nhien Tran, Yitong Liu, Yang Zhang, Aaron M Cypess, Andrew P White, Yuchen He, Rebecca Deng, Heiko Schöder, Joao A Paulo, Mark P Jedrychowski, Alexander S Banks, Yu-Hua Tseng, Paul Cohen, Linus T Tsai, Evan D Rosen, Samuel Klein, Maria Chondronikola, Fiona E McAllister, Nick Van Bruggen, Edward L Huttlin, Bruce M Spiegelman, Gary A Churchill, Steven P Gygi, Edward T Chouchani
Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins...
November 2, 2022: Cell
Anda M Chirila, Genelle Rankin, Shih-Yi Tseng, Alan J Emanuel, Carmine L Chavez-Martinez, Dawei Zhang, Christopher D Harvey, David D Ginty
The encoding of touch in the spinal cord dorsal horn (DH) and its influence on tactile representations in the brain are poorly understood. Using a range of mechanical stimuli applied to the skin, large-scale in vivo electrophysiological recordings, and genetic manipulations, here we show that neurons in the mouse spinal cord DH receive convergent inputs from both low- and high-threshold mechanoreceptor subtypes and exhibit one of six functionally distinct mechanical response profiles. Genetic disruption of DH feedforward or feedback inhibitory motifs, comprised of interneurons with distinct mechanical response profiles, revealed an extensively interconnected DH network that enables dynamic, flexible tuning of postsynaptic dorsal column (PSDC) output neurons and dictates how neurons in the primary somatosensory cortex respond to touch...
November 1, 2022: Cell
Charles A Herring, Rebecca K Simmons, Saskia Freytag, Daniel Poppe, Joel J D Moffet, Jahnvi Pflueger, Sam Buckberry, Dulce B Vargas-Landin, Olivier Clément, Enrique Goñi Echeverría, Gavin J Sutton, Alba Alvarez-Franco, Rui Hou, Christian Pflueger, Kerrie McDonald, Jose M Polo, Alistair R R Forrest, Anna K Nowak, Irina Voineagu, Luciano Martelotto, Ryan Lister
Human brain development is underpinned by cellular and molecular reconfigurations continuing into the third decade of life. To reveal cell dynamics orchestrating neural maturation, we profiled human prefrontal cortex gene expression and chromatin accessibility at single-cell resolution from gestation to adulthood. Integrative analyses define the dynamic trajectories of each cell type, revealing major gene expression reconfiguration at the prenatal-to-postnatal transition in all cell types followed by continuous reconfiguration into adulthood and identifying regulatory networks guiding cellular developmental programs, states, and functions...
October 27, 2022: Cell
Zhiyong Xie, Xianying Zhang, Miao Zhao, Lifang Huo, Meizhu Huang, Dapeng Li, Shuangfeng Zhang, Xinyu Cheng, Huating Gu, Chen Zhang, Cheng Zhan, Fengchao Wang, Congping Shang, Peng Cao
After ingestion of toxin-contaminated food, the brain initiates a series of defensive responses (e.g., nausea, retching, and vomiting). How the brain detects ingested toxin and coordinates diverse defensive responses remains poorly understood. Here, we developed a mouse-based paradigm to study defensive responses induced by bacterial toxins. Using this paradigm, we identified a set of molecularly defined gut-to-brain and brain circuits that jointly mediate toxin-induced defensive responses. The gut-to-brain circuit consists of a subset of Htr3a+ vagal sensory neurons that transmit toxin-related signals from intestinal enterochromaffin cells to Tac1+ neurons in the dorsal vagal complex (DVC)...
October 25, 2022: Cell
Cary R Boyd-Shiwarski, Daniel J Shiwarski, Shawn E Griffiths, Rebecca T Beacham, Logan Norrell, Daryl E Morrison, Jun Wang, Jacob Mann, William Tennant, Eric N Anderson, Jonathan Franks, Michael Calderon, Kelly A Connolly, Muhammad Umar Cheema, Claire J Weaver, Lubika J Nkashama, Claire C Weckerly, Katherine E Querry, Udai Bhan Pandey, Christopher J Donnelly, Dandan Sun, Aylin R Rodan, Arohan R Subramanya
When challenged by hypertonicity, dehydrated cells must recover their volume to survive. This process requires the phosphorylation-dependent regulation of SLC12 cation chloride transporters by WNK kinases, but how these kinases are activated by cell shrinkage remains unknown. Within seconds of cell exposure to hypertonicity, WNK1 concentrates into membraneless condensates, initiating a phosphorylation-dependent signal that drives net ion influx via the SLC12 cotransporters to restore cell volume. WNK1 condensate formation is driven by its intrinsically disordered C terminus, whose evolutionarily conserved signatures are necessary for efficient phase separation and volume recovery...
October 25, 2022: Cell
Li Wang, Kyungsuk Choi, Ting Su, Bing Li, Xiaofeng Wu, Ruihui Zhang, Jordan H Driskill, Hongde Li, Huiyan Lei, Pengfei Guo, Elizabeth H Chen, Yonggang Zheng, Duojia Pan
The function of biomolecular condensates is often restricted by condensate dissolution. Whether condensates can be suppressed without condensate dissolution is unclear. Here, we show that upstream regulators of the Hippo signaling pathway form functionally antagonizing condensates, and their coalescence into a common phase provides a mode of counteracting the function of biomolecular condensates without condensate dissolution. Specifically, the negative regulator SLMAP forms Hippo-inactivating condensates to facilitate pathway inhibition by the STRIPAK complex...
October 25, 2022: Cell
Faezzah Baharom, Ramiro A Ramirez-Valdez, Ahad Khalilnezhad, Shabnam Khalilnezhad, Marlon Dillon, Dalton Hermans, Sloane Fussell, Kennedy K S Tobin, Charles-Antoine Dutertre, Geoffrey M Lynn, Sören Müller, Florent Ginhoux, Andrew S Ishizuka, Robert A Seder
Therapeutic cancer vaccines are designed to increase tumor-specific T cell immunity. However, suppressive mechanisms within the tumor microenvironment (TME) may limit T cell function. Here, we assessed how the route of vaccination alters intratumoral myeloid cells. Using a self-assembling nanoparticle vaccine that links tumor antigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we treated tumor-bearing mice subcutaneously (SNP-SC) or intravenously (SNP-IV). Both routes generated antigen-specific CD8+ T cells that infiltrated tumors...
October 20, 2022: Cell
Maria Elena De Obaldia, Takeshi Morita, Laura C Dedmon, Daniel J Boehmler, Caroline S Jiang, Emely V Zeledon, Justin R Cross, Leslie B Vosshall
Some people are more attractive to mosquitoes than others, but the mechanistic basis of this phenomenon is poorly understood. We tested mosquito attraction to human skin odor and identified people who are exceptionally attractive or unattractive to mosquitoes. These differences were stable over several years. Chemical analysis revealed that highly attractive people produce significantly more carboxylic acids in their skin emanations. Mutant mosquitoes lacking the chemosensory co-receptors Ir8a, Ir25a, or Ir76b were severely impaired in attraction to human scent, but retained the ability to differentiate highly and weakly attractive people...
October 17, 2022: Cell
Tian Lu, Cheen Euong Ang, Xiaowei Zhuang
The recent development of spatial omics methods has enabled single-cell profiling of the transcriptome and 3D genome organization with high spatial resolution. Expanding the repertoire of spatial omics tools, a spatially resolved single-cell epigenomics method will accelerate understanding of the spatial regulation of cell and tissue functions. Here, we report a method for spatially resolved epigenomic profiling of single cells using in situ tagmentation and transcription followed by multiplexed imaging. We demonstrated the ability to profile histone modifications marking active promoters, putative enhancers, and silent promoters in individual cells, and generated high-resolution spatial atlas of hundreds of active promoters and putative enhancers in embryonic and adult mouse brains...
October 14, 2022: Cell
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