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        CIIA functions as a molecular switch for the Rac1-specific GEF activity of SOS1

        Hwang, Hyun Sub,Hwang, Sang Gil,Cho, Jun-Ho,Chae, Ji Soo,Yoon, Kyoung Wan,Cho, Ssang-Goo,Choi, Eui-Ju Rockefeller University Press 2011 The Journal of cell biology Vol.195 No.3

        <▼1><P>CIIA mediates the TGF-β–induced activation of SOS1–Rac1 signaling and cell migration.</P></▼1><▼2><P>Son of sevenless 1 (SOS1) is a dual guanine nucleotide exchange factor (GEF) that activates the guanosine triphosphatases Rac1 and Ras, which mediate signaling initiated by peptide growth factors. In this paper, we show that CIIA is a new binding partner of SOS1. CIIA promoted the SOS1–Rac1 interaction and inhibited the SOS1–Ras interaction. Furthermore, CIIA promoted the formation of an SOS1–EPS8 complex and SOS1-mediated Rac1 activation, whereas it inhibited SOS1-mediated activation of Ras. Transforming growth factor β (TGF-β) up-regulated the expression of CIIA and thereby promoted the association between CIIA and SOS1 in A549 human lung adenocarcinoma cells. Depletion of CIIA in these cells by ribonucleic acid interference inhibited the TGF-β–induced interaction between SOS1 and EPS8, activation of Rac1, and cell migration. Together, these results suggest that CIIA mediates the TGF-β–induced activation of SOS1–Rac1 signaling and cell migration in A549 cells. They further show that CIIA functions as a molecular switch for the GEF activity of SOS1, directing this activity toward Rac1.</P></▼2>

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        Multiple roles of lymphatic vessels in peripheral lymph node development

        Bovay, Esther,Sabine, Amé,lie,Prat-Luri, Borja,Kim, Sudong,Son, Kyungmin,Willrodt, Ann-Helen,Olsson, Cecilia,Halin, Cornelia,Kiefer, Friedemann,Betsholtz, Christer,Jeon, Noo Li,Luther, Sanjiv A. Rockefeller University Press 2018 The Journal of experimental medicine Vol.215 No.11

        <P>The mammalian lymphatic system consists of strategically located lymph nodes (LNs) embedded into a lymphatic vascular network. Mechanisms underlying development of this highly organized system are not fully understood. Using high-resolution imaging, we show that lymphoid tissue inducer (LTi) cells initially transmigrate from veins at LN development sites using gaps in venous mural coverage. This process is independent of lymphatic vasculature, but lymphatic vessels are indispensable for the transport of LTi cells that egress from blood capillaries elsewhere and serve as an essential LN expansion reservoir. At later stages, lymphatic collecting vessels ensure efficient LTi cell transport and formation of the LN capsule and subcapsular sinus. Perinodal lymphatics also promote local interstitial flow, which cooperates with lymphotoxin-β signaling to amplify stromal CXCL13 production and thereby promote LTi cell retention. Our data unify previous models of LN development by showing that lymphatics intervene at multiple points to assist LN expansion and identify a new role for mechanical forces in LN development.</P>

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        Romo1 is a mitochondrial nonselective cation channel with viroporin-like characteristics

        Lee, Gi Young,You, Deok-gyun,Lee, Hye-Ra,Hwang, Sun Wook,Lee, C. Justin,Yoo, Young Do Rockefeller University Press 2018 The Journal of cell biology Vol.217 No.6

        <P>Reactive oxygen species (ROS) modulator 1 (Romo1) is a nuclear-encoded mitochondrial inner membrane protein known to regulate mitochondrial ROS production and to act as an essential redox sensor in mitochondrial dynamics. Although its physiological roles have been studied for a decade, the biophysical mechanisms that explain these activities of Romo1 are unclear. In this study, we report that Romo1 is a unique mitochondrial ion channel that differs from currently identified eukaryotic ion channels. Romo1 is a highly conserved protein with structural features of class II viroporins, which are virus-encoded nonselective cation channels. Indeed, Romo1 forms a nonselective cation channel with its amphipathic helical transmembrane domain necessary for pore-forming activity. Notably, channel activity was specifically inhibited by Fe<SUP>2+</SUP> ions, an essential transition metal ion in ROS metabolism. Using structural bioinformatics, we designed an experimental data–guided structural model of Romo1 with a rational hexameric structure. We propose that Romo1 establishes a new category of viroporin-like nonselective cation channel in eukaryotes.</P>

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        Voltage-dependent regulation of Ca <sub>V</sub> 2.2 channels by G <sub>q</sub> -coupled receptor is facilitated by membrane-localized β subunit

        Keum, Dongil,Baek, Christina,Kim, Dong-Il,Kweon, Hae-Jin,Suh, Byung-Chang Rockefeller University Press 2014 The Journal of general physiology Vol.144 No.4

        <P>G protein–coupled receptors (GPCRs) signal through molecular messengers, such as Gβγ, Ca<SUP>2+</SUP>, and phosphatidylinositol 4,5-bisphosphate (PIP<SUB>2</SUB>), to modulate N-type voltage-gated Ca<SUP>2+</SUP> (Ca<SUB>V</SUB>2.2) channels, playing a crucial role in regulating synaptic transmission. However, the cellular pathways through which G<SUB>q</SUB>PCRs inhibit Ca<SUB>V</SUB>2.2 channel current are not completely understood. Here, we report that the location of Ca<SUB>V</SUB> β subunits is key to determining the voltage dependence of Ca<SUB>V</SUB>2.2 channel modulation by G<SUB>q</SUB>PCRs. Application of the muscarinic agonist oxotremorine-M to tsA-201 cells expressing M<SUB>1</SUB> receptors, together with Ca<SUB>V</SUB> N-type α1B, α2δ1, and membrane-localized β2a subunits, shifted the current-voltage relationship for Ca<SUB>V</SUB>2.2 activation 5 mV to the right and slowed current activation. Muscarinic suppression of Ca<SUB>V</SUB>2.2 activity was relieved by strong depolarizing prepulses. Moreover, when the C terminus of β-adrenergic receptor kinase (which binds Gβγ) was coexpressed with N-type channels, inhibition of Ca<SUB>V</SUB>2.2 current after M<SUB>1</SUB> receptor activation was markedly reduced and delayed, whereas the delay between PIP<SUB>2</SUB> hydrolysis and inhibition of Ca<SUB>V</SUB>2.2 current was decreased. When the Gβγ-insensitive Ca<SUB>V</SUB>2.2 α1C-1B chimera was expressed, voltage-dependent inhibition of calcium current was virtually abolished, suggesting that M<SUB>1</SUB> receptors act through Gβγ to inhibit Ca<SUB>V</SUB>2.2 channels bearing membrane-localized Ca<SUB>V</SUB> β2a subunits. Expression of cytosolic β subunits such as β2b and β3, as well as the palmitoylation-negative mutant β2a(C3,4S), reduced the voltage dependence of M<SUB>1</SUB> muscarinic inhibition of Ca<SUB>V</SUB>2.2 channels, whereas it increased inhibition mediated by PIP<SUB>2</SUB> depletion. Together, our results indicate that, with membrane-localized Ca<SUB>V</SUB> β subunits, Ca<SUB>V</SUB>2.2 channels are subject to Gβγ-mediated voltage-dependent inhibition, whereas cytosol-localized β subunits confer more effective PIP<SUB>2</SUB>-mediated voltage-independent regulation. Thus, the voltage dependence of G<SUB>q</SUB>PCR regulation of calcium channels can be determined by the location of isotype-specific Ca<SUB>V</SUB> β subunits.</P>

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        Caspase-8 controls the secretion of inflammatory lysyl-tRNA synthetase in exosomes from cancer cells

        Kim, Sang Bum,Kim, Hye Rim,Park, Min Chul,Cho, Seongmin,Goughnour, Peter C.,Han, Daeyoung,Yoon, Ina,Kim, YounHa,Kang, Taehee,Song, Eunjoo,Kim, Pilhan,Choi, Hyosun,Mun, Ji Young,Song, Chihong,Lee, Sang Rockefeller University Press 2017 The Journal of cell biology Vol.216 No.7

        <P>Aminoacyl-tRNA synthetases (ARSs), enzymes that normally control protein synthesis, can be secreted and have different activities in the extracellular space, but the mechanism of their secretion is not understood. This study describes the secretion route of the ARS lysyl-tRNA synthetase (KRS) and how this process is regulated by caspase activity, which has been implicated in the unconventional secretion of other proteins. We show that KRS is secreted from colorectal carcinoma cells within the lumen of exosomes that can trigger an inflammatory response. Caspase-8 cleaved the N-terminal of KRS, thus exposing a PDZ-binding motif located in the C terminus of KRS. Syntenin bound to the exposed PDZ-binding motif of KRS and facilitated the exosomic secretion of KRS dissociated from the multi-tRNA synthetase complex. KRS-containing exosomes released by cancer cells induced macrophage migration, and their secretion of TNF-α and cleaved KRS made a significant contribution to these activities, which suggests a novel mechanism by which caspase-8 may promote inflammation.</P>

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        Autism-like behavior caused by deletion of vaccinia-related kinase 3 is improved by TrkB stimulation

        Kang, Myung-Su,Choi, Tae-Yong,Ryu, Hye Guk,Lee, Dohyun,Lee, Seung-Hyun,Choi, Se-Young,Kim, Kyong-Tai Rockefeller University Press 2017 The Journal of experimental medicine Vol.214 No.10

        <P>Vaccinia-related kinases (VRKs) are multifaceted serine/threonine kinases that play essential roles in various aspects of cell signaling, cell cycle progression, apoptosis, and neuronal development and differentiation. However, the neuronal function of <I>VRK3</I> is still unknown despite its etiological potential in human autism spectrum disorder (ASD). Here, we report that <I>VRK3</I>-deficient mice exhibit typical symptoms of autism-like behavior, including hyperactivity, stereotyped behaviors, reduced social interaction, and impaired context-dependent spatial memory. A significant decrease in dendritic spine number and arborization were identified in the hippocampus CA1 of <I>VRK3</I>-deficient mice. These mice also exhibited a reduced rectification of AMPA receptor–mediated current and changes in expression of synaptic and signaling proteins, including tyrosine receptor kinase B (TrkB), Arc, and CaMKIIα. Notably, TrkB stimulation with 7,8-dihydroxyflavone reversed the altered synaptic structure and function and successfully restored autism-like behavior in <I>VRK3</I>-deficient mice. These results reveal that <I>VRK3</I> plays a critical role in neurodevelopmental disorders and suggest a potential therapeutic strategy for ASD.</P>

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        Tarantula Toxins Interact with Voltage Sensors within Lipid Membranes

        Milescu, Mirela,Vobecky, Jan,Roh, Soung H.,Kim, Sung H.,Jung, Hoi J.,Kim, Jae Il,Swartz, Kenton J. Rockefeller University Press 2007 The Journal of general physiology Vol.130 No.5

        <P>Voltage-activated ion channels are essential for electrical signaling, yet the mechanism of voltage sensing remains under intense investigation. The voltage-sensor paddle is a crucial structural motif in voltage-activated potassium (K<SUB>v</SUB>) channels that has been proposed to move at the protein–lipid interface in response to changes in membrane voltage. Here we explore whether tarantula toxins like hanatoxin and SGTx1 inhibit K<SUB>v</SUB> channels by interacting with paddle motifs within the membrane. We find that these toxins can partition into membranes under physiologically relevant conditions, but that the toxin–membrane interaction is not sufficient to inhibit K<SUB>v</SUB> channels. From mutagenesis studies we identify regions of the toxin involved in binding to the paddle motif, and those important for interacting with membranes. Modification of membranes with sphingomyelinase D dramatically alters the stability of the toxin–channel complex, suggesting that tarantula toxins interact with paddle motifs within the membrane and that they are sensitive detectors of lipid–channel interactions.</P>

      • A novel pathogenic role of the ER chaperone GRP78/BiP in rheumatoid arthritis

        Yoo, Seung-Ah,You, Sungyong,Yoon, Hyung-Ju,Kim, Dong-Ho,Kim, Hyun-Sook,Lee, Kyungho,Ahn, Jin Hee,Hwang, Daehee,Lee, Amy S.,Kim, Ki-Jo,Park, Yune-Jung,Cho, Chul-Soo,Kim, Wan-Uk The Rockefeller University Press 2012 The Journal of experimental medicine Vol.209 No.4

        <▼1><P>The ER chaperone GRP78/BiP is crucial for the development of rheumatoid arthritis.</P></▼1><▼2><P>An accumulation of misfolded proteins can trigger a cellular survival response in the endoplasmic reticulum (ER). In this study, we found that ER stress–associated gene signatures were highly expressed in rheumatoid arthritis (RA) synoviums and synovial cells. Proinflammatory cytokines, such as TNF and IL-1β, increased the expression of GRP78/BiP, a representative ER chaperone, in RA synoviocytes. RA synoviocytes expressed higher levels of GRP78 than osteoarthritis (OA) synoviocytes when stimulated by thapsigargin or proinflammatory cytokines. Down-regulation of <I>Grp78</I> transcripts increased the apoptosis of RA synoviocytes while abolishing TNF- or TGF-β–induced synoviocyte proliferation and cyclin D1 up-regulation. Conversely, overexpression of the <I>Grp78</I> gene prevented synoviocyte apoptosis. Moreover, <I>Grp78</I> small interfering RNA inhibited VEGF<SUB>165</SUB>-induced angiogenesis in vitro and also significantly impeded synoviocyte proliferation and angiogenesis in Matrigel implants engrafted into immunodeficient mice. Additionally, repeated intraarticular injections of BiP-inducible factor X, a selective GRP78 inducer, increased synoviocyte proliferation and angiogenesis in the joints of mice with experimental OA. In contrast, mice with <I>Grp78</I> haploinsufficiency exhibited the suppression of experimentally induced arthritis and developed a limited degree of synovial proliferation and angiogenesis. In summary, this study shows that the ER chaperone GRP78 is crucial for synoviocyte proliferation and angiogenesis, the pathological hallmark of RA.</P></▼2>

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