Cereal phytochromes: targets of selection, targets for manipulation?

Plants respond to shading through an adaptive syndrome termed shade avoidance. In high-density crop plantings, shade avoidance generally increases extension growth at the expense of yield and can be at odds with the agronomic performance of the crop as a whole. Studies in Arabidopsis are beginning to reveal the essential role phytochromes play in regulating this process and to identify genes underlying the response. In this article, we focus on how phytochrome signaling networks have been targeted in cereal breeding programs in the past and discuss the potential to alter these pathways through breeding and transgenic manipulation to develop crops that perform better under typical high density conditions.     

Calpains: targets of cataract prevention?

There is emerging evidence to suggest that the unregulated Ca(2+)-mediated proteolysis of essential lens proteins by calpains might be a major contributor to some forms of cataract in both animals and humans. Moreover, recently solved calpain structures have revealed molecular-level details of the activation mechanism used by these proteases, enabling the structure-based design of potent calpain inhibitors with the potential to act as anti-cataract agents. These agents offer the first real hope of an urgently needed alternative to the surgical treatment of at least some forms of cataract and relief from a life-depreciating condition on a global scale.     

Conservation targets for viable species assemblages?

Estimates of minimum areas required for effective biodiversity conservation differ substantially. Scientific reserve design and placement procedures indicate that between 30 and 75% of any region may be required to sample biodiversity features. These estimates do not routinely incorporate measures for sampling viable populations of species or explore the area requirements of sampling viable populations of species assemblages. To determine the area requirements for sampling viable populations of a herbivore assemblage, spatially explicit abundance data from the Kruger National Park, South Africa, were analyzed. Area requirements were consistently above 50% and were unaffected by selected target population sizes. In addition, area requirements appeared to be insensitive to selection unit size (analytical grain), habitat quality, the coarseness of the land classification system used or the presence of low-density species. Thus, traditional conservation area targets of 10–15% appear inadequate for representing viable populations of a herbivore assemblage from African savanna regions. This suggests that conservation targets of at least 50% of land classification units may represent a more appropriate conservation rule of thumb, or alternatively, that the use of data independent conservation targets may need to be abandoned.     

IFN-γ-mediated neuronal defense mechanism targets Toxoplasma

Toxoplasma gondii encysts preferentially within neurons in the central nervous system, establishing lifelong persistence. Despite recent discoveries, this neuronal preference was thought, in part, to be secondary to a lack of neuronal cell-autonomous immunity. By showing that neurons can mount interferon-gamma (IFN-γ)-mediated cell-autonomous anti-T. gondii defenses, Chandrasekaran et al. have challenged long held assumptions.     

VGLUTs--potential targets for the treatment of seizures?

Vesicular glutamate transporters (VGLUTs) load glutamate into synaptic vesicles. In this issue of Neuron, Juge et?al. report that ketone bodies compete with chloride-dependent activation of VGLUTs, leading to suppression of glutamate release and seizures. These findings provide a surprising explanation for the efficacy of the ketogenic diet in controlling epilepsy.     

Has nature already identified all useful antibacterial targets?

Novel antimicrobial targets are urgently needed to overcome rising antibiotic resistance of important human pathogens. However, evidence from previous antimicrobial screenings, in silico analysis, and experimental target evaluation suggests that the number of novel bacterial broad-spectrum targets might be severely limited. This is because of the poor conservation of genes among diverse bacterial pathogens, partial functional redundancy and nutrient-rich host environments. Remaining opportunities under these circumstances include the development of narrow-spectrum antibiotics against specific pathogens and the exploration of target combinations.     

How do site-specific DNA-binding proteins find their targets?

Essentially all the biological functions of DNA depend on site-specific DNA-binding proteins finding their targets, and therefore ‘searching’ through megabases of non-target DNA. In this article, we review current understanding of how this sequence searching is done. We review how simple diffusion through solution may be unable to account for the rapid rates of association observed in experiments on some model systems, primarily the Lac repressor. We then present a simplified version of the ‘facilitated diffusion’ model of Berg, Winter and von Hippel, showing how non-specific DNA–protein interactions may account for accelerated targeting, by permitting the protein to sample many binding sites per DNA encounter. We discuss the 1-dimensional ‘sliding’ motion of protein along non-specific DNA, often proposed to be the mechanism of this multiple site sampling, and we discuss the role of short-range diffusive ‘hopping’ motions. We then derive the optimal range of sliding for a few physical situations, including simple models of chromosomes in vivo, showing that a sliding range of ~100 bp before dissociation optimizes targeting in vivo. Going beyond first-order binding kinetics, we discuss how processivity, the interaction of a protein with two or more targets on the same DNA, can reveal the extent of sliding and we review recent experiments studying processivity using the restriction enzyme EcoRV. Finally, we discuss how single molecule techniques might be used to study the dynamics of DNA site-specific targeting of proteins.     

Influenza-virus-induced signaling cascades: targets for antiviral therapy?

Influenza viruses continue to pose a severe threat worldwide, causing thousands of deaths and an enormous economic loss every year. The major problem in fighting influenza is the high genetic variability of the virus, resulting in the rapid formation of variants that escape the acquired immunity against previous virus strains, or have resistance to antiviral agents. Every virus depends on its host cell and, hence, cellular functions that are essential for viral replication might be suitable targets for antiviral therapy. As a result, intracellular signaling cascades induced by the virus, in particular mitogen-activated protein kinase pathways, have recently come into focus.     

Transgenesis and yield: what are our targets?

Plant metabolic engineering has been used to generate a wide range of transgenic lines in which specific metabolic steps have been targeted. Attempts to increase yield of some agronomically important crops using this approach have highlighted the inherent complexities of modulating plant metabolism. In light of the recent findings by Regierer et al. this article addresses the major challenges faced with respect to enhancing yield through transgenesis.     

Arenavirus nucleoprotein targets interferon regulatory factor-activating kinase IKKε

Arenaviruses perturb innate antiviral defense by blocking induction of type I interferon (IFN) production. Accordingly, the arenavirus nucleoprotein (NP) was shown to block activation and nuclear translocation of interferon regulatory factor 3 (IRF3) in response to virus infection. Here, we sought to identify cellular factors involved in innate antiviral signaling targeted by arenavirus NP. Consistent with previous studies, infection with the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) prevented phosphorylation of IRF3 in response to infection with Sendai virus, a strong inducer of the retinoic acid-inducible gene I (RIG-I)/mitochondrial antiviral signaling (MAVS) pathway of innate antiviral signaling. Using a combination of coimmunoprecipitation and confocal microscopy, we found that LCMV NP associates with the IκB kinase (IKK)-related kinase IKKε but that, rather unexpectedly, LCMV NP did not bind to the closely related TANK-binding kinase 1 (TBK-1). The NP-IKKε interaction was highly conserved among arenaviruses from different clades. In LCMV-infected cells, IKKε colocalized with NP but not with MAVS located on the outer membrane of mitochondria. LCMV NP bound the kinase domain (KD) of IKKε (IKBKE) and blocked its autocatalytic activity and its ability to phosphorylate IRF3, without undergoing phosphorylation. Together, our data identify IKKε as a novel target of arenavirus NP. Engagement of NP seems to sequester IKKε in an inactive complex. Considering the important functions of IKKε in innate antiviral immunity and other cellular processes, the NP-IKKε interaction likely plays a crucial role in arenavirus-host interaction.     

CNGCs: prime targets of plant cyclic nucleotide signalling?

Cyclic nucleotide-gated channels (CNGCs) are a recently identified family of plant ion channels. They show a high degree of similarity to Shaker-type voltage-gated channels and contain a C-terminal cyclic nucleotide-binding domain with an overlapping calmodulin-binding domain. Heterologously expressed plant CNGCs show activation by cyclic nucleotides and permeability to monovalent and divalent cations. In plants, downstream effectors of cyclic nucleotide signals have so far remained obscure, and CNGCs might be their prime targets. The unique position of CNGCs as ligand-gated Ca(2+)-permeable channels suggests that they function at key sites where cyclic nucleotide and Ca(2+) signalling pathways interact. Such processes include plant defence responses, and two recently characterized Arabidopsis mutants in CNGC genes indeed show altered pathogen responses.