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Rong Tan, Satoshi Nakajima, Qun Wang, Hongxiang Sun, Jing Xue, Jian Wu, Sabine Hellwig, Xuemei Zeng, Nathan A Yates, Thomas E Smithgall, Ming Lei, Yu Jiang, Arthur S Levine, Bing Su, Li Lan
Telomeric repeat binding factor 1 (TRF1) is essential to the maintenance of telomere chromatin structure and integrity. However, how telomere integrity is maintained, especially in response to damage, remains poorly understood. Here, we identify Nek7, a member of the Never in Mitosis Gene A (NIMA) kinase family, as a regulator of telomere integrity. Nek7 is recruited to telomeres and stabilizes TRF1 at telomeres after damage in an ATM activation-dependent manner. Nek7 deficiency leads to telomere aberrations, long-lasting γH2AX and 53BP1 foci, and augmented cell death upon oxidative telomeric DNA damage...
March 2, 2017: Molecular Cell
Chong-Shan Shi, John H Kehrl
The release of cytochrome c from the inner mitochondrial membrane, where it is anchored by caridolipin, triggers the formation of the Apaf-1 apoptosome. Cardiolipin also interacts with NLRP3 recruiting NLRP3 to mitochondria and facilitating inflammasome assembly. In this study we investigated whether cytosolic cytochrome c impacts NLRP3 inflammasome activation in macrophages. We report that cytochrome c binds to the LRR domain of NLRP3 and that cytochrome c reduces the interactions between NLRP3 and cardiolipin and between NLRP3 and NEK7, a recently recognized component of the NLRP3 inflammasome needed for NLRP3 oligomerization...
2016: PloS One
Vladimir Lažetić, David S Fay
Molting is an essential developmental process in nematodes during which the epidermal apical extracellular matrix, the cuticle, is remodeled to accommodate further growth. Using genetic approaches, we identified a requirement for three conserved ankyrin repeat-rich proteins, MLT-2/ANKS6, MLT-3/ANKS3, and MLT-4/INVS, in Caenorhabditis elegans molting. Loss of mlt function resulted in severe defects in the ability of larvae to shed old cuticle and led to developmental arrest. Genetic analyses demonstrated that MLT proteins functionally cooperate with the conserved NIMA kinase family members NEKL-2/NEK8 and NEKL-3/NEK6/NEK7 to promote cuticle shedding...
January 2017: Genetics
Christina J Groß, Ritu Mishra, Katharina S Schneider, Guillaume Médard, Jennifer Wettmarshausen, Daniela C Dittlein, Hexin Shi, Oliver Gorka, Paul-Albert Koenig, Stephan Fromm, Giovanni Magnani, Tamara Ćiković, Lara Hartjes, Joachim Smollich, Avril A B Robertson, Matthew A Cooper, Marc Schmidt-Supprian, Michael Schuster, Kate Schroder, Petr Broz, Claudia Traidl-Hoffmann, Bruce Beutler, Bernhard Kuster, Jürgen Ruland, Sabine Schneider, Fabiana Perocchi, Olaf Groß
Imiquimod is a small-molecule ligand of Toll-like receptor-7 (TLR7) that is licensed for the treatment of viral infections and cancers of the skin. Imiquimod has TLR7-independent activities that are mechanistically unexplained, including NLRP3 inflammasome activation in myeloid cells and apoptosis induction in cancer cells. We investigated the mechanism of inflammasome activation by imiquimod and the related molecule CL097 and determined that K(+) efflux was dispensable for NLRP3 activation by these compounds...
October 18, 2016: Immunity
Jin Xu, Liqun Lu, Lanfang Li
No abstract text is available yet for this article.
October 2016: Acta Biochimica et Biophysica Sinica
Stefan Wolf, Weilin Wu, Cheryl Jones, Olivia Perwitasari, Suresh Mahalingam, Ralph A Tripp
Influenza A viruses are important pathogens of humans and animals. While seasonal influenza viruses infect humans every year, occasionally animal-origin viruses emerge to cause pandemics with significantly higher morbidity and mortality rates. In March 2013, the public health authorities of China reported three cases of laboratory confirmed human infection with avian influenza A (H7N9) virus, and subsequently there have been many cases reported across South East Asia and recently in North America. Most patients experience severe respiratory illness, and morbidity with mortality rates near 40%...
2016: PloS One
Irsan E Kooi, Berber M Mol, Maarten P G Massink, Marcus C de Jong, Pim de Graaf, Paul van der Valk, Hanne Meijers-Heijboer, Gertjan J L Kaspers, Annette C Moll, Hein Te Riele, Jacqueline Cloos, Josephine C Dorsman
BACKGROUND: While RB1 loss initiates retinoblastoma development, additional somatic copy number alterations (SCNAs) can drive tumor progression. Although SCNAs have been identified with good concordance between studies at a cytoband resolution, accurate identification of single genes for all recurrent SCNAs is still challenging. This study presents a comprehensive meta-analysis of genome-wide SCNAs integrated with gene expression profiling data, narrowing down the list of plausible retinoblastoma driver genes...
2016: PloS One
Lei Zhou, Zhixin Wang, Xinsen Xu, Yong Wan, Kai Qu, Haining Fan, Qiangpu Chen, Xuejun Sun, Chang Liu
NIMA-related kinase-7 (Nek7) is a serine/threonine kinase involved in cell-cycle progression via mitotic spindle formation and cytokinesis. In this study, we investigated whether Nek7 involves in hepatocellular carcinoma (HCC). Interestingly, we found that Nek7 was significantly overexpressed in HCC than in liver tissues. In HCC patients, high Nek7 expression was significantly correlated with tumor numbers, tumor diameter, adjacent organs invasion, tumor grade and TNM stage. Furthermore, Nek7 expression pattern showed close relationship with that of Ki-67, a well-stablished cell proliferation marker...
April 5, 2016: Oncotarget
Yuan He, Melody Y Zeng, Dahai Yang, Benny Motro, Gabriel Núñez
Inflammasomes are intracellular protein complexes that drive the activation of inflammatory caspases. So far, four inflammasomes involving NLRP1, NLRP3, NLRC4 and AIM2 have been described that recruit the common adaptor protein ASC to activate caspase-1, leading to the secretion of mature IL-1β and IL-18 proteins. The NLRP3 inflammasome has been implicated in the pathogenesis of several acquired inflammatory diseases as well as cryopyrin-associated periodic fever syndromes (CAPS) caused by inherited NLRP3 mutations...
February 18, 2016: Nature
Hexin Shi, Ying Wang, Xiaohong Li, Xiaoming Zhan, Miao Tang, Maggy Fina, Lijing Su, David Pratt, Chun Hui Bu, Sara Hildebrand, Stephen Lyon, Lindsay Scott, Jiexia Quan, Qihua Sun, Jamie Russell, Stephanie Arnett, Peter Jurek, Ding Chen, Vladimir V Kravchenko, John C Mathison, Eva Marie Y Moresco, Nancy L Monson, Richard J Ulevitch, Bruce Beutler
The NLRP3 inflammasome responds to microbes and danger signals by processing and activating proinflammatory cytokines, including interleukin 1β (IL-1β) and IL-18. We found here that activation of the NLRP3 inflammasome was restricted to interphase of the cell cycle by NEK7, a serine-threonine kinase previously linked to mitosis. Activation of the NLRP3 inflammasome required NEK7, which bound to the leucine-rich repeat domain of NLRP3 in a kinase-independent manner downstream of the induction of mitochondrial reactive oxygen species (ROS)...
March 2016: Nature Immunology
Jonathan L Schmid-Burgk, Dhruv Chauhan, Tobias Schmidt, Thomas S Ebert, Julia Reinhardt, Elmar Endl, Veit Hornung
Inflammasomes are high molecular weight protein complexes that assemble in the cytosol upon pathogen encounter. This results in caspase-1-dependent pro-inflammatory cytokine maturation, as well as a special type of cell death, known as pyroptosis. The Nlrp3 inflammasome plays a pivotal role in pathogen defense, but at the same time, its activity has also been implicated in many common sterile inflammatory conditions. To this effect, several studies have identified Nlrp3 inflammasome engagement in a number of common human diseases such as atherosclerosis, type 2 diabetes, Alzheimer disease, or gout...
January 1, 2016: Journal of Biological Chemistry
Tamanna Haq, Mark W Richards, Selena G Burgess, Pablo Gallego, Sharon Yeoh, Laura O'Regan, David Reverter, Joan Roig, Andrew M Fry, Richard Bayliss
Mitotic spindle assembly requires the regulated activities of protein kinases such as Nek7 and Nek9. Nek7 is autoinhibited by the protrusion of Tyr97 into the active site and activated by the Nek9 non-catalytic C-terminal domain (CTD). CTD binding apparently releases autoinhibition because mutation of Tyr97 to phenylalanine increases Nek7 activity independently of Nek9. Here we find that self-association of the Nek9-CTD is needed for Nek7 activation. We map the minimal Nek7 binding region of Nek9 to residues 810-828...
November 2, 2015: Nature Communications
Haribaskar Ramachandran, Christina Engel, Barbara Müller, Jörn Dengjel, Gerd Walz, Toma A Yakulov
Nephronophthisis (NPH) is an autosomal recessive cystic kidney disease, and a frequent cause of end-stage renal failure in children. To date, 17 NPH-associated gene products (NPHPs) have been identified. Most NPHPs participate in large multi-protein complexes that localize to the cilium and/or basal body; however, the precise composition of these complexes and their biological function remain largely unknown. We recently observed that the ankyrin repeat protein Anks3 interacts with the NPH family member Anks6...
August 28, 2015: Biochemical and Biophysical Research Communications
Daniel T Rogerson, Amit Sachdeva, Kaihang Wang, Tamanna Haq, Agne Kazlauskaite, Susan M Hancock, Nicolas Huguenin-Dezot, Miratul M K Muqit, Andrew M Fry, Richard Bayliss, Jason W Chin
Serine phosphorylation is a key post-translational modification that regulates diverse biological processes. Powerful analytical methods have identified thousands of phosphorylation sites, but many of their functions remain to be deciphered. A key to understanding the function of protein phosphorylation is access to phosphorylated proteins, but this is often challenging or impossible. Here we evolve an orthogonal aminoacyl-tRNA synthetase/tRNACUA pair that directs the efficient incorporation of phosphoserine (pSer (1)) into recombinant proteins in Escherichia coli...
July 2015: Nature Chemical Biology
Amar Joshi, Yvette Newbatt, P Craig McAndrew, Mark Stubbs, Rosemary Burke, Mark W Richards, Chitra Bhatia, John J Caldwell, Tatiana McHardy, Ian Collins, Richard Bayliss
IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although the conservation of the underlying molecular mechanism is not clear from existing structures. We have crystallized human IRE1 in a back-to-back conformation only previously seen for the yeast homologue. In our structure the kinase domain appears primed for catalysis but the RNase domains are disengaged...
May 30, 2015: Oncotarget
Edmarcia Elisa de Souza, Heidi Hehnly, Arina Marina Perez, Gabriela Vaz Meirelles, Juliana Helena Costa Smetana, Stephen Doxsey, Jörg Kobarg
The mitotic spindle apparatus is composed of microtubule (MT) networks attached to kinetochores organized from 2 centrosomes (a.k.a. spindle poles). In addition to this central spindle apparatus, astral MTs assemble at the mitotic spindle pole and attach to the cell cortex to ensure appropriate spindle orientation. We propose that cell cycle-related kinase, Nek7, and its novel interacting protein RGS2, are involved in mitosis regulation and spindle formation. We found that RGS2 localizes to the mitotic spindle in a Nek7-dependent manner, and along with Nek7 contributes to spindle morphology and mitotic spindle pole integrity...
2015: Cell Cycle
Eduardo Cruz Moraes, Gabriela Vaz Meirelles, Rodrigo Vargas Honorato, Tatiana de Arruda Campos Brasil de Souza, Edmarcia Elisa de Souza, Mario Tyago Murakami, Paulo Sergio Lopes de Oliveira, Jörg Kobarg
Human Neks are a conserved protein kinase family related to cell cycle progression and cell division and are considered potential drug targets for the treatment of cancer and other pathologies. We screened the activation loop mutant kinases hNek1 and hNek2, wild-type hNek7, and five hNek6 variants in different activation/phosphorylation statesand compared them against 85 compounds using thermal shift denaturation. We identified three compounds with significant Tm shifts: JNK Inhibitor II for hNek1(Δ262-1258)-(T162A), Isogranulatimide for hNek6(S206A), andGSK-3 Inhibitor XIII for hNek7wt...
January 13, 2015: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
John Yochem, Vladimir Lažetić, Leslie Bell, Lihsia Chen, David Fay
Caenorhabditis elegans molting is a process during which the apical extracellular matrix of the epidermis, the cuticle, is remodeled through a process of degradation and re-synthesis. Using a genetic approach, we identified nekl-3 as essential for the completion of molting. NEKL-3 is highly similar to the mammalian NEK kinase family members NEK6 and NEK7. Animals homozygous for a hypomorphic mutation in nekl-3, sv3, had a novel molting defect in which the central body region, but not the head or tail, was unable to shed the old cuticle...
February 15, 2015: Developmental Biology
Vassiliki Saloura, Hyun-Soo Cho, Kazuma Kiyotani, Houda Alachkar, Zhixiang Zuo, Makoto Nakakido, Tatsuhiko Tsunoda, Tanguy Seiwert, Mark Lingen, Jonathan Licht, Yusuke Nakamura, Ryuji Hamamoto
UNLABELLED: Squamous cell carcinoma of the head and neck (SCCHN) is a relatively common malignancy with suboptimal long-term prognosis, thus new treatment strategies are urgently needed. Over the last decade, histone methyltransferases (HMT) have been recognized as promising targets for cancer therapy, but their mechanism of action in most solid tumors, including SCCHN, remains to be elucidated. This study investigated the role of Wolf-Hirschhorn syndrome candidate 1 (WHSC1), an NSD family HMT, in SCCHN...
February 2015: Molecular Cancer Research: MCR
Edmarcia Elisa de Souza, Gabriela Vaz Meirelles, Bárbara Biatriz Godoy, Arina Marina Perez, Juliana Helena Costa Smetana, Stephen J Doxsey, Mark E McComb, Catherine E Costello, Stephen A Whelan, Jörg Kobarg
Human NEK7 is a regulator of cell division and plays an important role in growth and survival of mammalian cells. Human NEK6 and NEK7 are closely related, consisting of a conserved C-terminal catalytic domain and a nonconserved and disordered N-terminal regulatory domain, crucial to mediate the interactions with their respective proteins. Here, in order to better understand NEK7 cellular functions, we characterize the NEK7 interactome by two screening approaches: one using a yeast two-hybrid system and the other based on immunoprecipitation followed by mass spectrometry analysis...
September 5, 2014: Journal of Proteome Research
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