Introduction

Autism, inflammatory bowel disease, and MMR vaccine

BJU InternationalVolume 89, Issue 7 p. 793-794 Chronic ethanol consumption impairs adrenoceptor- and purinoceptor-mediated relaxations in isolated rat detrusor smooth muscle R.C. Calvert MA, MB, Bchir, MRCS, R.C. Calvert MA, MB, Bchir, MRCS Research Registrar Departments of Urology and Clinical Biochemistry, Royal Free and University College Medical School (Royal Free Campus), University College London, UKSearch for more papers by this authorF.C.L. Banks MB, BS, FRCS, F.C.L. Banks MB, BS, FRCS Research Registrar Departments of Urology and Clinical Biochemistry, Royal Free and University College Medical School (Royal Free Campus), University College London, UKSearch for more papers by this authorC.S. Thompson PhD, C.S. Thompson PhD Senior Research Fellow Departments of Urology and Clinical Biochemistry, Royal Free and University College Medical School (Royal Free Campus), University College London, UKSearch for more papers by this authorD.P. Mikhailidis MB, BS, FRCPath, MD, D.P. Mikhailidis MB, BS, FRCPath, MD Reader Departments of Urology and Clinical Biochemistry, Royal Free and University College Medical School (Royal Free Campus), University College London, UKSearch for more papers by this authorR.J. Morgan MA, BM, Bchir, FRCS, R.J. Morgan MA, BM, Bchir, FRCS Consultant Urological Surgeon Departments of Urology and Clinical Biochemistry, Royal Free and University College Medical School (Royal Free Campus), University College London, UKSearch for more papers by this author R.C. Calvert MA, MB, Bchir, MRCS, R.C. Calvert MA, MB, Bchir, MRCS Research Registrar Departments of Urology and Clinical Biochemistry, Royal Free and University College Medical School (Royal Free Campus), University College London, UKSearch for more papers by this authorF.C.L. Banks MB, BS, FRCS, F.C.L. Banks MB, BS, FRCS Research Registrar Departments of Urology and Clinical Biochemistry, Royal Free and University College Medical School (Royal Free Campus), University College London, UKSearch for more papers by this authorC.S. Thompson PhD, C.S. Thompson PhD Senior Research Fellow Departments of Urology and Clinical Biochemistry, Royal Free and University College Medical School (Royal Free Campus), University College London, UKSearch for more papers by this authorD.P. Mikhailidis MB, BS, FRCPath, MD, D.P. Mikhailidis MB, BS, FRCPath, MD Reader Departments of Urology and Clinical Biochemistry, Royal Free and University College Medical School (Royal Free Campus), University College London, UKSearch for more papers by this authorR.J. Morgan MA, BM, Bchir, FRCS, R.J. Morgan MA, BM, Bchir, FRCS Consultant Urological Surgeon Departments of Urology and Clinical Biochemistry, Royal Free and University College Medical School (Royal Free Campus), University College London, UKSearch for more papers by this author First published: 01 May 2002 https://doi.org/10.1046/j.1464-410X.2002.t01-4-02801.xCitations: 4Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume89, Issue7May 2002Pages 793-794 RelatedInformation

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A critical role of influenza A virus nonstructural protein 1 (NS1) is to antagonize the host cellular antiviral response. NS1 accomplishes this role through numerous interactions with host proteins, including the cytoplasmic pathogen recognition receptor, retinoic acid–inducible gene I (RIG-I). Although the consequences of this interaction have been studied, the complete mechanism by which NS1 antagonizes RIG-I signaling remains unclear. We demonstrated previously that the NS1 RNA-binding domain (NS1RBD) interacts directly with the second caspase activation and recruitment domain (CARD) of RIG-I. We also identified that a single strain-specific polymorphism in the NS1RBD (R21Q) completely abrogates this interaction. Here we investigate the functional consequences of an R21Q mutation on NS1's ability to antagonize RIG-I signaling. We observed that an influenza virus harboring the R21Q mutation in NS1 results in significant up-regulation of RIG-I signaling. In support of this, we determined that an R21Q mutation in NS1 results in a marked deficit in NS1's ability to antagonize TRIM25-mediated ubiquitination of the RIG-I CARDs, a critical step in RIG-I activation. We also observed that WT NS1 is capable of binding directly to the tandem RIG-I CARDs, whereas the R21Q mutation in NS1 significantly inhibits this interaction. Furthermore, we determined that the R21Q mutation does not impede the interaction between NS1 and TRIM25 or NS1RBD's ability to bind RNA. The data presented here offer significant insights into NS1 antagonism of RIG-I and illustrate the importance of understanding the role of strain-specific polymorphisms in the context of this specific NS1 function. A critical role of influenza A virus nonstructural protein 1 (NS1) is to antagonize the host cellular antiviral response. NS1 accomplishes this role through numerous interactions with host proteins, including the cytoplasmic pathogen recognition receptor, retinoic acid–inducible gene I (RIG-I). Although the consequences of this interaction have been studied, the complete mechanism by which NS1 antagonizes RIG-I signaling remains unclear. We demonstrated previously that the NS1 RNA-binding domain (NS1RBD) interacts directly with the second caspase activation and recruitment domain (CARD) of RIG-I. We also identified that a single strain-specific polymorphism in the NS1RBD (R21Q) completely abrogates this interaction. Here we investigate the functional consequences of an R21Q mutation on NS1's ability to antagonize RIG-I signaling. We observed that an influenza virus harboring the R21Q mutation in NS1 results in significant up-regulation of RIG-I signaling. In support of this, we determined that an R21Q mutation in NS1 results in a marked deficit in NS1's ability to antagonize TRIM25-mediated ubiquitination of the RIG-I CARDs, a critical step in RIG-I activation. We also observed that WT NS1 is capable of binding directly to the tandem RIG-I CARDs, whereas the R21Q mutation in NS1 significantly inhibits this interaction. Furthermore, we determined that the R21Q mutation does not impede the interaction between NS1 and TRIM25 or NS1RBD's ability to bind RNA. The data presented here offer significant insights into NS1 antagonism of RIG-I and illustrate the importance of understanding the role of strain-specific polymorphisms in the context of this specific NS1 function.

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How cells utilize nutrients to produce the ATP needed for bioenergetic homeostasis has been well-characterized. What is less well-studied is how resting cells metabolically shift from an ATP-producing catabolic metabolism to a metabolism that supports anabolic growth. In metazoan organisms, the discovery of growth factors and the ability of their receptors to induce new transcription and translation led to the hypothesis that the bioenergetic and synthetic demands of cell growth were primarily met through the replacement of nutrients consumed during net macromolecular synthesis, a demand-based system of nutrient uptake. Recent data have challenged this hypothesis. Instead, there is increasing evidence that cellular nutrient uptake is a push system. Growth factor signaling has been linked to direct stimulation of nutrient uptake. The ability of growth factor signaling to increase the uptake of glucose, lipids, and amino acids to levels that exceed a cell's bioenergetic and synthetic needs has been documented in a wide variety of settings. In some tissues, this leads to the storage of the excess nutrients in the form of glycogen or fat. In others, the excess is secreted as lactate and certain nonessential amino acids. When growth factor signaling stimulates nutrient uptake to levels that exceed a cell's bioenergetic needs, adaptive changes in intermediate metabolism lead to the production of anabolic precursors that fuel the net synthesis of protein, lipids, and nucleic acids. Through the increased production of these precursors, growth factor signaling provides a supply-side stimulation of cell growth and proliferation.