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8 Janelia Publications

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    04/29/22 | Cryo-EM structure of the EBV ribonucleotide reductase BORF2 and mechanism of APOBEC3B inhibition.
    Shaban NM, Yan R, Shi K, Moraes SN, Cheng AZ, Carpenter MA, McLellan JS, Yu Z, Harris RS
    Science Advances. 2022 Apr 29;8(17):eabm2827. doi: 10.1126/sciadv.abm2827

    Viruses use a plethora of mechanisms to evade immune responses. A recent example is neutralization of the nuclear DNA cytosine deaminase APOBEC3B by the Epstein-Barr virus (EBV) ribonucleotide reductase subunit BORF2. Cryo-EM studies of APOBEC3B-BORF2 complexes reveal a large >1000-Å binding surface composed of multiple structural elements from each protein, which effectively blocks the APOBEC3B active site from accessing single-stranded DNA substrates. Evolutionary optimization is suggested by unique insertions in BORF2 absent from other ribonucleotide reductases and preferential binding to APOBEC3B relative to the highly related APOBEC3A and APOBEC3G enzymes. A molecular understanding of this pathogen-host interaction has potential to inform the development of drugs that block the interaction and liberate the natural antiviral activity of APOBEC3B. In addition, given a role for APOBEC3B in cancer mutagenesis, it may also be possible for information from the interaction to be used to develop DNA deaminase inhibitors.

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    04/25/22 | Regulation of Drosophila courtship behavior by the Tlx/tailless-like nuclear receptor, dissatisfaction.
    Duckhorn JC, Cande J, Metkus MC, Song H, Altamirano S, Stern DL, Shirangi TR
    Current Biology. 2022 Apr 25;32(8):1703-1714. doi: 10.1016/j.cub.2022.02.031

    Sexually dimorphic courtship behaviors in Drosophila melanogaster develop from the activity of the sexual differentiation genes, doublesex (dsx) and fruitless (fru), functioning with other regulatory factors that have received little attention. The dissatisfaction (dsf) gene encodes an orphan nuclear receptor homologous to vertebrate Tlx and Drosophila tailless that is critical for the development of several aspects of female- and male-specific sexual behaviors. Here, we report the pattern of dsf expression in the central nervous system and show that the activity of sexually dimorphic abdominal interneurons that co-express dsf and dsx is necessary and sufficient for vaginal plate opening in virgin females, ovipositor extrusion in mated females, and abdominal curling in males during courtship. We find that dsf activity results in different neuroanatomical outcomes in females and males, promoting and suppressing, respectively, female development and function of these neurons depending upon the sexual state of dsx expression. We posit that dsf and dsx interact to specify sex differences in the neural circuitry for dimorphic abdominal behaviors.

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    04/22/22 | ESCRT-mediated membrane repair protects tumor-derived cells against T cell attack.
    Ritter AT, Shtengel G, Xu CS, Weigel A, Hoffman DP, Freeman M, Iyer N, Alivodej N, Ackerman D, Voskoboinik I, Trapani J, Hess HF, Mellman I
    Science. 2022 Apr 22;376(6591):377-382. doi: 10.1126/science.abl3855

    Cytotoxic T lymphocytes (CTLs) and natural killer cells kill virus-infected and tumor cells through the polarized release of perforin and granzymes. Perforin is a pore-forming toxin that creates a lesion in the plasma membrane of the target cell through which granzymes enter the cytosol and initiate apoptosis. Endosomal sorting complexes required for transport (ESCRT) proteins are involved in the repair of small membrane wounds. We found that ESCRT proteins were precisely recruited in target cells to sites of CTL engagement immediately after perforin release. Inhibition of ESCRT machinery in cancer-derived cells enhanced their susceptibility to CTL-mediated killing. Thus, repair of perforin pores by ESCRT machinery limits granzyme entry into the cytosol, potentially enabling target cells to resist cytolytic attack.

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    04/19/22 | Nuclear lamin isoforms differentially contribute to LINC complex-dependent nucleocytoskeletal coupling and whole-cell mechanics.
    Vahabikashi A, Sivagurunathan S, Nicdao FA, Han YL, Park CY, Kittisopikul M, Wong X, Tran JR, Gundersen GG, Reddy KL, Luxton GW, Guo M, Fredberg JJ, Zheng Y, Adam SA, Goldman RD
    Proceedings of the National Academy of Sciences of the U.S.A.. 2022 Apr 19;119(17):e2121816119. doi: 10.1073/pnas.2121816119

    SignificanceInteractions between the cell nucleus and cytoskeleton regulate cell mechanics and are facilitated by the interplay between the nuclear lamina and linker of nucleoskeleton and cytoskeleton (LINC) complexes. To date, the specific contribution of the four lamin isoforms to nucleocytoskeletal connectivity and whole-cell mechanics remains unknown. We discover that A- and B-type lamins distinctively interact with LINC complexes that bind F-actin and vimentin filaments to differentially modulate cortical stiffness, cytoplasmic stiffness, and contractility of mouse embryonic fibroblasts (MEFs). We propose and experimentally verify an integrated lamin-LINC complex-cytoskeleton model that explains cellular mechanical phenotypes in lamin-deficient MEFs. Our findings uncover potential mechanisms for cellular defects in human laminopathies and many cancers associated with mutations or modifications in lamin isoforms.

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    04/15/22 | Systematic characterization of wing mechanosensors that monitor airflow and wing deformations.
    Fabian J, Siwanowicz I, Uhrhan M, Maeda M, Bomphrey RJ, Lin H
    iScience. 2022 Apr 15;25(4):104150. doi: 10.1016/j.isci.2022.104150

    Animal wings deform during flight in ways that can enhance lift, facilitate flight control, and mitigate damage. Monitoring the structural and aerodynamic state of the wing is challenging because deformations are passive, and the flow fields are unsteady; it requires distributed mechanosensors that respond to local airflow and strain on the wing. Without a complete map of the sensor arrays, it is impossible to model control strategies underpinned by them. Here, we present the first systematic characterization of mechanosensors on the dragonfly's wings: morphology, distribution, and wiring. By combining a cross-species survey of sensor distribution with quantitative neuroanatomy and a high-fidelity finite element analysis, we show that the mechanosensors are well placed to perceive features of the wing dynamics relevant to flight. This work describes the wing sensory apparatus in its entirety and advances our understanding of the sensorimotor loop that facilitates exquisite flight control in animals with highly deformable wings.

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    04/11/22 | BRD2 compartmentalizes the accessible genome.
    Xie L, Dong P, Qi Y, Hsieh TS, English BP, Jung S, Chen X, De Marzio M, Casellas R, Chang HY, Zhang B, Tjian R, Liu Z
    Nature Genetics. 2022 Apr 11;54(4):481-491. doi: 10.1038/s41588-022-01044-9

    Mammalian chromosomes are organized into megabase-sized compartments that are further subdivided into topologically associating domains (TADs). While the formation of TADs is dependent on cohesin, the mechanism behind compartmentalization remains enigmatic. Here, we show that the bromodomain and extraterminal (BET) family scaffold protein BRD2 promotes spatial mixing and compartmentalization of active chromatin after cohesin loss. This activity is independent of transcription but requires BRD2 to recognize acetylated targets through its double bromodomain and interact with binding partners with its low-complexity domain. Notably, genome compartmentalization mediated by BRD2 is antagonized on the one hand by cohesin and on the other hand by the BET homolog protein BRD4, both of which inhibit BRD2 binding to chromatin. Polymer simulation of our data supports a BRD2-cohesin interplay model of nuclear topology, in which genome compartmentalization results from a competition between loop extrusion and chromatin-state-specific affinity interactions.

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    04/06/22 | Voltage imaging identifies spinal circuits that modulate locomotor adaptation in zebrafish.
    Böhm UL, Kimura Y, Kawashima T, Ahrens MB, Higashijima S, Engert F, Cohen AE
    Neuron. 2022 Apr 06;110(7):1211-1222.e4. doi: 10.1016/j.neuron.2022.01.001

    Motor systems must continuously adapt their output to maintain a desired trajectory. While the spinal circuits underlying rhythmic locomotion are well described, little is known about how the network modulates its output strength. A major challenge has been the difficulty of recording from spinal neurons during behavior. Here, we use voltage imaging to map the membrane potential of large populations of glutamatergic neurons throughout the spinal cord of the larval zebrafish during fictive swimming in a virtual environment. We characterized a previously undescribed subpopulation of tonic-spiking ventral V3 neurons whose spike rate correlated with swimming strength and bout length. Optogenetic activation of V3 neurons led to stronger swimming and longer bouts but did not affect tail beat frequency. Genetic ablation of V3 neurons led to reduced locomotor adaptation. The power of voltage imaging allowed us to identify V3 neurons as a critical driver of locomotor adaptation in zebrafish.

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    Darshan Lab
    04/05/22 | Learning to represent continuous variables in heterogeneous neural networks
    Ran Darshan , Alexander Rivkind
    Cell Reports. 2022 Apr 05;39(1):110612. doi: 10.1016/j.celrep.2022.110612

    Manifold attractors are a key framework for understanding how continuous variables, such as position or head direction, are encoded in the brain. In this framework, the variable is represented along a continuum of persistent neuronal states which forms a manifold attactor. Neural networks with symmetric synaptic connectivity that can implement manifold attractors have become the dominant model in this framework. In addition to a symmetric connectome, these networks imply homogeneity of individual-neuron tuning curves and symmetry of the representational space; these features are largely inconsistent with neurobiological data. Here, we developed a theory for computations based on manifold attractors in trained neural networks and show how these manifolds can cope with diverse neuronal responses, imperfections in the geometry of the manifold and a high level of synaptic heterogeneity. In such heterogeneous trained networks, a continuous representational space emerges from a small set of stimuli used for training. Furthermore, we find that the network response to external inputs depends on the geometry of the representation and on the level of synaptic heterogeneity in an analytically tractable and interpretable way. Finally, we show that a too complex geometry of the neuronal representation impairs the attractiveness of the manifold and may lead to its destabilization. Our framework reveals that continuous features can be represented in the recurrent dynamics of heterogeneous networks without assuming unrealistic symmetry. It suggests that the representational space of putative manifold attractors in the brain dictates the dynamics in their vicinity.

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