Kinesin-12 Kif15 Targets Kinetochore Fibers through an Intrinsic Two-Step Mechanism

Sturgill, Emma G.,Das, D.,Takizawa, Y.,Shin, Y.,Collier, Scott E.,Ohi, Melanie D.,Hwang, W.,Lang, Matthew J.,Ohi, R. Current Biology Ltd ; Elsevier Science Ltd 2014 Current biology Vol.24 No.19

Proteins that recognize and act on specific subsets of microtubules (MTs) enable the varied functions of the MT cytoskeleton. We recently discovered that Kif15 localizes exclusively to kinetochore fibers (K-fibers) [1, 2] or bundles of kinetochore-MTs within the mitotic spindle. It is currently speculated that the MT-associated protein TPX2 loads Kif15 onto spindle MTs [3-5], but this model has not been rigorously tested. Here, we show that Kif15 accumulates on MT bundles as a consequence of two inherent biochemical properties. First, Kif15 is self-repressed by its C terminus. Second, Kif15 harbors a nonmotor MT-binding site, enabling dimeric Kif15 to crosslink and slide MTs. Two-MT binding activates Kif15, resulting in its accumulation on and motility within MT bundles but not on individual MTs. We propose that Kif15 targets K-fibers via an intrinsic two-step mechanism involving molecular unfolding and two-MT binding. This work challenges the current model of Kif15 regulation and provides the first account of a kinesin that specifically recognizes a higher-order MT array.

Inhibition of Respiration Extends C. elegans Life Span via Reactive Oxygen Species that Increase HIF-1 Activity

Lee, S.J.,Hwang, A.B.,Kenyon, C. Current Biology Ltd ; Elsevier Science Ltd 2010 Current biology Vol.20 No.23

A mild inhibition of mitochondrial respiration extends the life span of many organisms, including yeast, worms, flies, and mice [1-10], but the underlying mechanism is unknown. One environmental condition that reduces rates of respiration is hypoxia (low oxygen). Thus, it is possible that mechanisms that sense oxygen play a role in the longevity response to reduced respiration. The hypoxia-inducible factor HIF-1 is a highly conserved transcription factor that activates genes that promote survival during hypoxia [11, 12]. In this study, we show that inhibition of respiration in C. elegans can promote longevity by activating HIF-1. Through genome-wide screening, we found that RNA interference (RNAi) knockdown of many genes encoding respiratory-chain components induced hif-1-dependent transcription. Moreover, HIF-1 was required for the extended life spans of clk-1 and isp-1 mutants, which have reduced rates of respiration [1, 4, 13]. Inhibiting respiration appears to activate HIF-1 by elevating the level of reactive oxygen species (ROS). We found that ROS are increased in respiration mutants and that mild increases in ROS can stimulate HIF-1 to activate gene expression and promote longevity. In this way, HIF-1 appears to link respiratory stress in the mitochondria to a nuclear transcriptional response that promotes longevity.

Emergence of plant vascular system: roles of hormonal and non-hormonal regulatory networks

Cho, H.,Dang, T.V.T.,Hwang, I. Current Biology, Ltd ; Elsevier Science Ltd 2017 Current opinion in plant biology Vol.35 No.-

<P>The divergence of land plants followed by vascular plants has entirely changed the terrestrial ecology. The vascular system is a prerequisite for this evolutionary event, providing upright stature and communication for sink demand-source capacity and facilitating the development of plants and colonization over a wide range of environmental habitats. Various hormonal and non-hormonal regulatory networks have been identified and reviewed as key processes for vascular formation; however, how these factors have evolutionarily emerged and interconnected to trigger the emergence of the vascular system still remains elusive. Here, to understand the intricacy of cross talks among these factors, we highlight how core hormonal signaling and transcriptional networks are coalesced into the appearance of vascular plants during evolution.</P>

Regulatory network of NAC transcription factors in leaf senescence

Kim, H.J.,Nam, H.G.,Lim, P.O. Current Biology, Ltd ; Elsevier Science Ltd 2016 Current opinion in plant biology Vol.33 No.-

<P>Leaf senescence is finely tuned by many regulatory factors such as NAC (NAM/ATAF/CUC)) transcription factors (TFs). NACs comprise one of the largest families of TFs in plants, many of which are differentially regulated during leaf senescence and play a major role in leaf senescence. Recent studies advanced our understanding on the structural and functional features of NAC TFs including target binding specificities of the N-terminal DNA binding domain and dynamic interaction of the C-terminal intrinsically disordered domain with other proteins. NAC TFs control other NACs and also interact with NACs or other TFs to fine-tune the expression of target genes. These studies clearly demonstrated the highly complex characteristics of NAC regulatory networks, which are dynamically regulated temporally and spatially and effectively integrate multiple developmental and environmental signals.</P>

Adaptation through horizontal gene transfer in the cryptoendolithic red alga Galdieria phlegrea

Qiu, H.,Price, D.C.,Weber, A.P.M.,Reeb, V.,Chan Yang, E.,Lee, J.M.,Kim, S.Y.,Yoon, H.S.,Bhattacharya, D. Current Biology Ltd ; Elsevier Science Ltd 2013 Current biology Vol.23 No.19

Thriving in the hot, acidic, and metal-rich environments associated with geothermal areas is possible for only a few eukaryotes, with the Cyanidiophytina red algae (Cyanidium, Galdieria, and Cyanidioschyzon) being a famous example. These unicellular taxa can live in pH 0-4 and temperatures reaching up to 56<SUP>o</SUP>C [1,2]. Because Cyanidiophytina is sister to a vast array of mesophilic red algae (the Rhodophytina), such as the unicellular Porphyridium and the seaweed Chondrus[3], the genetic basis of their adaptation to extreme environments is of great interest from both the perspective of biotechnology and of evolution. The recently completed 13.7 Mbp genome sequence from the hot-spring dwelling Galdieria sulphuraria demonstrated that horizontal gene transfer (HGT) from prokaryotic sources provided this taxon with remarkable metabolic versatility (e.g., glycerol metabolism) and the ability to survive in its hostile environment (e.g., genes to detoxify mercury and arsenic) [4]. To explore the role of HGT in other members of this genus, we generated an 11.4 Mbp draft genome assembly from the sister taxon G. phlegrea DBV 009 [5]. In contrast to G. sulphuraria, this species is adapted to dry habitats near fumaroles such as fissures between rocks or cryptoendolithic environments [5,6]. Here, we provide evidence for extensive gene loss in the common ancestor of Cyanidiophytina that includes the eukaryote-derived loci required for urea utilization. Surprisingly, we find that G. phlegrea has regained the complete set of genes required for urea hydrolysis through HGT from eubacteria. The unlinked nature of these genes is likely explained by multiple gene transfers that resulted in assembly of the pathway in G. phlegrea. Our study demonstrates that genome reduction, a common outcome in eukaryotes for adaptation to a specialized niche, can be ameliorated by the gain of once lost, or novel functions through HGT.

Monocular Perceptual Deprivation from Interocular Suppression Temporarily Imbalances Ocular Dominance

Kim, H.W.,Kim, C.Y.,Blake, R. Current Biology Ltd ; Elsevier Science Ltd 2017 Current Biology Vol.27 No.6

<P>Early visual experience sculpts neural mechanisms that regulate the balance of influence exerted by the two eyes on cortical mechanisms underlying binocular vision [1, 2], and experience's impact on this neural balancing act continues into adulthood [3-5]. One recently described, compelling example of adult neural plasticity is the effect of patching one eye for a relatively short period of time: contrary to intuition, monocular visual deprivation actually improves the deprived eye's competitive advantage during a subsequent period of binocular rivalry [6-8], the robust form of visual competition prompted by dissimilar stimulation of the two eyes [9, 10]. Neural concomitants of this improvement in monocular dominance are reflected in measurements of brain responsiveness following eye patching [11, 12]. Here we report that patching an eye is unnecessary for producing this paradoxical deprivation effect: interocular suppression of an ordinarily visible stimulus being viewed by one eye is sufficient to produce shifts in subsequent predominance of that eye to an extent comparable to that produced by patching the eye. Moreover, this imbalance in eye dominance can also be induced by prior, extended viewing of two monocular images differing only in contrast. Regardless of how shifts in eye dominance are induced, the effect decays once the two eyes view stimuli equal in strength. These novel findings implicate the operation of interocular neural gain control that dynamically adjusts the relative balance of activity between the two eyes [13, 14].</P>

Mitigating health risks associated with alcoholic beverages through metabolic engineering

Jayakody, L.N.,Lane, S.,Kim, H.,Jin, Y.S. Current Biology ; Elsevier Science Ltd 2016 Current opinion in biotechnology Vol.37 No.-

Epidemiological studies have established a positive relationship between the occurrence of cancer and consumption of alcoholic beverages. Metabolic engineering of brewing yeast to reduce potential carcinogenic compounds in alcoholic beverage is technically feasible as well as economically promising. This review presents the mechanisms of formation of potentially carcinogenic components in alcoholic beverages, such as formaldehyde, acetaldehyde, ethyl carbamate, acrylamide, and heavy metals, and introduces effective genetic perturbations to minimize the concentrations of these harmful components. As precise and effective genome editing tools for polyploid yeast are now available, we envision that yeast metabolic engineering might open up new research directions for improving brewing yeast in order to ensure product safety as well as to increase overall quality of alcoholic beverages.

Identification of Orai1 Channel Inhibitors by Using Minimal Functional Domains to Screen Small Molecule Microarrays

Sadaghiani, A.,Lee, S.,Odegaard, Justin I.,Leveson-Gower, Dennis B.,McPherson, Olivia M.,Novick, P.,Kim, M.,Koehler, Angela N.,Negrin, R.,Dolmetsch, Ricardo E.,Park, C. Current Biology Ltd ; Elsevier Science Ltd 2014 Chemistry & biology Vol.21 No.10

Store-operated calcium (SOC) channels are vital for activation of the immune cells, and mutations in the channel result in severe combined immunodeficiency in human patients. In lymphocytes, SOC entry is mediated by the Orai1 channel, which is activated by direct binding of STIM1. Here we describe an alternative approach for identifying inhibitors of SOC entry using minimal functional domains of STIM1 and Orai1 to screen a small-molecule microarray. This screen identified AnCoA4, which inhibits SOC entry at submicromolar concentrations and blocks T cell activation in vitro and in vivo. Biophysical studies revealed that AnCoA4 binds to the C terminus of Orai1, directly inhibiting calcium influx through the channel and also reducing binding of STIM1. AnCoA4, unlike other reported SOC inhibitors, is a molecule with a known binding site and mechanism of action. These studies also provide proof of principle for an approach to ion channel drug discovery.

Editorial overview: Food biotechnology: Critical gap filler in the nexus of food, energy, and waste for a prosperous future

Seo, J.H.,Jin, Y.S. Current Biology ; Elsevier Science Ltd 2016 Current opinion in biotechnology Vol.37 No.-

Unbiased Proteomic Profiling Strategy for Discovery of Bacterial Effector Proteins Reveals that Salmonella Protein PheA Is a Host Cell Cycle Regulator

Na, H.N.,Yoo, Y.H.,Yoon, C.,Lee, J.S. Current Biology Ltd ; Elsevier Science Ltd 2015 Chemistry & biology Vol.22 No.4

Salmonella utilizes a type III secretion system to inject bacterial effector proteins into the host cell cytosol. Once in the cytosol, these effectors hijack various biochemical pathways to regulate virulence. Despite the importance of effector proteins, especially for understanding host-pathogen interactions, a potentially large number of effectors are yet to be identified. Here, we demonstrate that unbiased chemical proteomic profiling using off-the-shelf fluorescent probes leads to the discovery of a host cell cycle regulator encoded in the Salmonella genome. Our profiling combined with bioinformatic analysis implicates 29 Salmonella as potential effectors. We follow up on the top candidate, chorismate mutase-P/prehenate dehydratase, PheA, and present evidence that PheA is an effector that mimics E2F7 transcription factor of the host cell and promotes G1/S cell cycle arrest. This validates our strategy and opens opportunities for effector identification in the future.