A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells

Nature Biotechnology
Joao T MarquesBryan R G Williams

Abstract

Nonspecific effects triggered by small interfering RNAs (siRNAs) complicate the use of RNA interference (RNAi) to specifically downregulate gene expression. To uncover the basis of these nonspecific activities, we analyzed the effect of chemically synthesized siRNAs on mammalian double-stranded RNA (dsRNA)-activated signaling pathways. siRNAs ranging from 21 to 27 nucleotides (nt) in length activated the interferon system when they lacked 2-nt 3' overhangs, a characteristic of Dicer products. We show that the recognition of siRNAs is mediated by the RNA helicase RIG-I and that the presence of 3' overhangs impairs its ability to unwind the dsRNA substrate and activate downstream signaling to the transcription factor IRF-3. These results suggest a structural basis for discrimination between microRNAs that are endogenous Dicer products, and nonself dsRNAs such as by-products of viral replication. These findings will enable the rational design of siRNAs that avoid nonspecific effects or, alternatively, that induce bystander effects to potentially increase the efficacy of siRNA-based treatments of viral infections or cancer.

References

Nov 1, 1992·Molecular and Cellular Biology·L MancheM B Mathews
Feb 7, 2001·Genes & Development·S M ElbashirT Tuschl
Aug 2, 2001·Proceedings of the National Academy of Sciences of the United States of America·N J CaplenR A Morgan
Apr 25, 2002·Proceedings of the National Academy of Sciences of the United States of America·Kristi L PetersGanes C Sen
May 29, 2003·Nucleic Acids Research·Frank CzaudernaJörg Kaufmann
Aug 28, 2003·Nature Cell Biology·Carol A SledzBryan R G Williams
Mar 3, 2004·Nature Biotechnology·Dong-Ho KimJohn J Rossi
May 22, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Katalin KarikóDrew Weissman
Jun 30, 2004·Nature Immunology·David E Levy, Isabelle J Marié
Sep 17, 2004·Nature·Victor Ambros
Dec 22, 2004·Molecular Cell·Bryan R Cullen
Dec 28, 2004·Nature Biotechnology·Despina SiolasMichele A Cleary
Dec 28, 2004·Nature Biotechnology·Dong-Ho KimJohn J Rossi
Mar 22, 2005·Nature Biotechnology·Adam D JudgeIan MacLachlan
Jul 26, 2005·Immunity·Hiroki KatoShizuo Akira
Jul 29, 2005·Nucleic Acids Research·Scott D RoseMark A Behlke
Aug 17, 2005·Journal of Virology·Joao T MarquesBryan R G Williams
Nov 8, 2005·Nature Biotechnology·Joao T Marques, Bryan R G Williams
Jan 18, 2006·Immunity·Daniel B Stetson, Ruslan Medzhitov
Jan 27, 2006·Nature·John D Baxter, Paul Webb

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Citations

Nov 3, 2009·Amino Acids·Alina Baum, Adolfo García-Sastre
Apr 1, 2010·Journal of Clinical Immunology·Jan Rehwinkel
Oct 29, 2011·Pharmaceutical Research·Saurabh SinghRam I Mahato
Jul 31, 2013·Immunobiology·Martin Schlee
Jun 4, 2013·Trends in Microbiology·Claudia Gürtler, Andrew G Bowie
Oct 2, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Kenneth A HowardJørgen Kjems
May 13, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Martin Schlee, Gunther Hartmann
Dec 22, 2011·Molecular Therapy : the Journal of the American Society of Gene Therapy·Garrett R Rettig, Mark A Behlke
Jan 19, 2012·Molecular Therapy : the Journal of the American Society of Gene Therapy·Rosemary L KanastyDaniel G Anderson
Apr 10, 2013·Molecular Therapy : the Journal of the American Society of Gene Therapy·Tommy A Karlsen, Jan E Brinchmann
May 9, 2006·Nature Biotechnology·Mouldy Sioud
Jan 2, 2007·Nature Biotechnology·Parag MallickRuedi Aebersold
Nov 8, 2008·Nature Medicine·Fabio Petrocca, Judy Lieberman
Aug 25, 2006·Nature Methods·Yi Pei, Thomas Tuschl
Apr 5, 2007·Nature Protocols·Mohammed AmarzguiouiJohn J Rossi
May 12, 2010·Nature Reviews. Rheumatology·David S Pisetsky, Peter E Lipsky
Jan 11, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Marc S WeinbergPatrick Arbuthnot
Aug 30, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Masayuki SanoJohn J Rossi
Jun 6, 2008·Journal de la Société de biologie·François DautryMaria-Antonietta Buccheri
Jan 6, 2009·Proceedings of the National Academy of Sciences of the United States of America·Daisy W LeungGaya K Amarasinghe
May 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Wenyi GuNigel A J McMillan
Sep 2, 2010·Proceedings of the National Academy of Sciences of the United States of America·Alina BaumAdolfo García-Sastre
Jan 12, 2011·Proceedings of the National Academy of Sciences of the United States of America·Erica S MachlinSelena M Sagan
Nov 21, 2008·The Journal of Biological Chemistry·C T Ranjith-KumarCheng C Kao
Nov 26, 2008·The Journal of Biological Chemistry·Christopher S McAllister, Charles E Samuel
Mar 13, 2009·The Journal of Biological Chemistry·Xiaojun LiPingwei Li
Jul 2, 2008·The Journal of Experimental Medicine·Takeshi Saito, Michael Gale
Jan 31, 2008·Human Gene Therapy·Adam Judge, Ian MacLachlan
Sep 26, 2007·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Michael P GantierSeamas C Donnelly
Apr 29, 2008·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Maryam Zamanian-DaryoushBryan R G Williams
May 1, 2012·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Alexandra ForsbachJörg Vollmer
May 10, 2013·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Isaque João da Silva de FariaJoão Trindade Marques
Jul 14, 2011·Nucleic Acid Therapeutics·Chan Il ChangDong-ki Lee
Jul 22, 2008·Oligonucleotides·Michael A CollingwoodMark A Behlke
Nov 26, 2008·Oligonucleotides·Mark A Behlke
May 16, 2009·Oligonucleotides·Marjorie RobbinsIan MacLachlan
Feb 28, 2009·International Immunology·Taro Kawai, Shizuo Akira
Sep 26, 2006·Nucleic Acids Research·Alexey EpanchintsevHeiko Hermeking

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