Gastric Helicobacter pylori Infection Affects Local and Distant Microbial Populations and Host Responses

Publication date: Available online 4 February 2016
Source:Cell Reports
Author(s): Sabine Kienesberger, Laura M. Cox, Alexandra Livanos, Xue-Song Zhang, Jennifer Chung, Guillermo I. Perez-Perez, Gregor Gorkiewicz, Ellen L. Zechner, Martin J. Blaser
Helicobacter pylori is a late-in-life human pathogen with potential early-life benefits. Although H. pylori is disappearing from the human population, little is known about the influence of H. pylori on the host’s microbiota and immunity. Studying the interactions of H. pylori with murine hosts over 6 months, we found stable colonization accompanied by gastric histologic and antibody responses. Analysis of gastric and pulmonary tissues revealed increased expression of multiple immune response genes, conserved across mice and over time in the stomach and more transiently in the lungs. Moreover, H. pylori infection led to significantly different population structures in both the gastric and intestinal microbiota. These studies indicate that H. pylori influences the microbiota and host immune responses not only locally in the stomach, but distantly as well, affecting important target organs.

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Kienesberger et al. utilize a mouse model to study H. pylori infections over 6 months. They report that H. pylori significantly affects the population structure of the gastric and intestinal microbiota. The infection alters gastric immune and inflammatory responses and causes distant effects via altered hormones and immunity.


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Subcellular Imbalances in Synaptic Activity

Publication date: Available online 4 February 2016
Source:Cell Reports
Author(s): Naoya Takahashi, Chiaki Kobayashi, Tomoe Ishikawa, Yuji Ikegaya
The dynamic interactions between synaptic excitation and inhibition (E/I) shape membrane potential fluctuations and determine patterns of neuronal outputs; however, the spatiotemporal organization of these interactions within a single cell is poorly understood. Here, we investigated the relationship between local synaptic excitation and global inhibition in hippocampal pyramidal neurons using functional dendrite imaging in combination with whole-cell recordings of inhibitory postsynaptic currents. We found that the sums of spine inputs over dendritic trees were counterbalanced by a proportional amount of somatic inhibitory inputs. This online E/I correlation was maintained in dendritic segments that were longer than 50 μm. However, at the single spine level, only 22% of the active spines were activated with inhibitory inputs. This inhibition-coupled activity occurred mainly in the spines with large heads. These results shed light on a microscopic E/I-balancing mechanism that operates at selected synapses and that may increase the accuracy of neural information.

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Takahashi et al. find that, although global GABAergic inhibition counterbalances synaptic excitation on dendritic trees, this balance breaks down at the microscopic level since only large synapses are excited by this inhibition.


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Ligand-Induced Receptor-like Kinase Complex Regulates Floral Organ Abscission in Arabidopsis

Publication date: Available online 4 February 2016
Source:Cell Reports
Author(s): Xiangzong Meng, Jinggeng Zhou, Jiao Tang, Bo Li, Marcos V.V. de Oliveira, Jijie Chai, Ping He, Libo Shan
Abscission is a developmental process that enables plants to shed unwanted organs. In Arabidopsis, the floral organ abscission is regulated by a signaling pathway consisting of the peptide ligand IDA, the receptor-like kinases (RLKs) HAE and HSL2, and a downstream MAP kinase (MAPK) cascade. However, little is known about the molecular link between ligand-receptor pairs and intracellular signaling. Here, we report that the SERK family RLKs function redundantly in regulating floral organ abscission downstream of IDA and upstream of the MAPK cascade. IDA induces heterodimerization of HAE/HSL2 and SERKs, which transphosphorylate each other. The SERK3 residues mediating its interaction with the immune receptor FLS2 and the brassinosteroid receptor BRI1 are also required for IDA-induced HAE/HSL2-SERK3 interaction, suggesting SERKs serve as co-receptors of HAE/HSL2 in perceiving IDA. Thus, our study reveals the signaling activation mechanism in floral organ abscission by IDA-induced HAE/HSL2-SERK complex formation accompanied by transphosphorylation.

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Meng et al. show that the Arabidopsis SERK family receptor-like kinases (RLKs) regulate floral organ abscission via the ligand-induced interaction and transphosphorylation with the HAE and HSL2 receptors and reveal the receptor activation mechanism in an important plant developmental process.


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Post-translational Regulation of Cas9 during G1 Enhances Homology-Directed Repair

Publication date: Available online 4 February 2016
Source:Cell Reports
Author(s): Tony Gutschner, Monika Haemmerle, Giannicola Genovese, Giulio F. Draetta, Lynda Chin
CRISPR/Cas9 induces DNA double-strand breaks that are repaired by cell-autonomous repair pathways, namely, non-homologous end-joining (NHEJ), or homology-directed repair (HDR). While HDR is absent in G1, NHEJ is active throughout the cell cycle and, thus, is largely favored over HDR. We devised a strategy to increase HDR by directly synchronizing the expression of Cas9 with cell-cycle progression. Fusion of Cas9 to the N-terminal region of human Geminin converted this gene-editing protein into a substrate for the E3 ubiquitin ligase complex APC/Cdh1, resulting in a cell-cycle-tailored expression with low levels in G1 but high expression in S/G2/M. Importantly, Cas9-hGem(1/110) increased the rate of HDR by up to 87% compared to wild-type Cas9. Future developments may enable high-resolution expression of genome engineering proteins, which might increase HDR rates further, and may contribute to a better understanding of DNA repair pathways due to spatiotemporal control of DNA damage induction.

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Using a protein engineering approach, Gutschner et al. generate a Cas9 fusion protein to control genome editing in time and space. Coupling Cas9 protein levels to cell-cycle dynamics results in higher site-specific integration events.


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Zebrafish Embryonic Lipidomic Analysis Reveals that the Yolk Cell Is Metabolically Active in Processing Lipid

Publication date: Available online 4 February 2016
Source:Cell Reports
Author(s): Daniel Fraher, Andrew Sanigorski, Natalie A. Mellett, Peter J. Meikle, Andrew J. Sinclair, Yann Gibert
The role of lipids in providing energy and structural cellular components during vertebrate development is poorly understood. To elucidate these roles further, we visualized lipid deposition and examined expression of key lipid-regulating genes during zebrafish embryogenesis. We also conducted a semiquantitative analysis of lipidomic composition using liquid chromatography (LC)-mass spectrometry. Finally, we analyzed processing of boron-dipyrromethene (BODIPY) lipid analogs injected into the yolk using thin layer chromatography. Our data reveal that the most abundant lipids in the embryo are cholesterol, phosphatidylcholine, and triglyceride. Moreover, we demonstrate that lipids are processed within the yolk prior to mobilization to the embryonic body. Our data identify a metabolically active yolk and body resulting in a dynamic lipid composition. This provides a foundation for studying lipid biology during normal or pharmacologically compromised embryogenesis.

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Fraher et al. develop a method to identify lipids separately in the zebrafish yolk and the embryonic body. Lipid usage and content are dynamic in the yolk and embryo during development. The yolk actively processes lipids prior to migration to the body during early embryogenesis.


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ATRIP Deacetylation by SIRT2 Drives ATR Checkpoint Activation by Promoting Binding to RPA-ssDNA

Publication date: Available online 4 February 2016
Source:Cell Reports
Author(s): Hui Zhang, PamelaSara E. Head, Waaqo Daddacha, Seong-Hoon Park, Xingzhe Li, Yunfeng Pan, Matthew Z. Madden, Duc M. Duong, Maohua Xie, Bing Yu, Matthew D. Warren, Elaine A. Liu, Vishal R. Dhere, Chunyang Li, Ivan Pradilla, Mylin A. Torres, Ya Wang, William S. Dynan, Paul W. Doetsch, Xingming Deng, Nicholas T. Seyfried, David Gius, David S. Yu
The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase checkpoint pathway maintains genome integrity; however, the role of the sirtuin 2 (SIRT2) acetylome in regulating this pathway is not clear. We found that deacetylation of ATR-interacting protein (ATRIP), a regulatory partner of ATR, by SIRT2 potentiates the ATR checkpoint. SIRT2 interacts with and deacetylates ATRIP at lysine 32 (K32) in response to replication stress. SIRT2 deacetylation of ATRIP at K32 drives ATR autophosphorylation and signaling and facilitates DNA replication fork progression and recovery of stalled replication forks. K32 deacetylation by SIRT2 further promotes ATRIP accumulation to DNA damage sites and binding to replication protein A-coated single-stranded DNA (RPA-ssDNA). Collectively, these results support a model in which ATRIP deacetylation by SIRT2 promotes ATR-ATRIP binding to RPA-ssDNA to drive ATR activation and thus facilitate recovery from replication stress, outlining a mechanism by which the ATR checkpoint is regulated by SIRT2 through deacetylation.

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Zhang et al. demonstrate that ATRIP deacetylation at conserved lysine 32 by SIRT2 promotes ATR-ATRIP binding to RPA-ssDNA to drive ATR activation and thus facilitate recovery from replication stress.


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PRMT7 Preserves Satellite Cell Regenerative Capacity

Publication date: Available online 4 February 2016
Source:Cell Reports
Author(s): Roméo Sébastien Blanc, Gillian Vogel, Taiping Chen, Colin Crist, Stéphane Richard
Regeneration of skeletal muscle requires the continued presence of quiescent muscle stem cells (satellite cells), which become activated in response to injury. Here, we report that whole-body protein arginine methyltransferase PRMT7^−/− adult mice and mice conditionally lacking PRMT7 in satellite cells using Pax7-CreERT2 both display a significant reduction in satellite cell function, leading to defects in regenerative capacity upon muscle injury. We show that PRMT7 is preferentially expressed in activated satellite cells and, interestingly, PRMT7-deficient satellite cells undergo cell-cycle arrest and premature cellular senescence. These defects underlie poor satellite cell stem cell capacity to regenerate muscle and self-renew after injury. PRMT7-deficient satellite cells express elevated levels of the CDK inhibitor p21CIP1 and low levels of its repressor, DNMT3b. Restoration of DNMT3b in PRMT7-deficient cells rescues PRMT7-mediated senescence. Our findings define PRMT7 as a regulator of the DNMT3b/p21 axis required to maintain muscle stem cell regenerative capacity.

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Decline of muscle stem cell function is associated with both intrinsic and extrinsic factors. Blanc et al. show that the protein arginine methyltransferase PRMT7 regulates the p21/DNMT3b axis in muscle stem cells to preserve their intrinsic capacity to self-renew and to fully regenerate muscles in adult mice.


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