Piscataway, NJ – Many viruses infecting humans including influenza virus, hepatitis C virus, West Nile virus, rabies and measles viruses contain a ribonucleic acid (RNA) genome. These viruses are dependent on RNA as genetic information and they duplicate in human cells to make copies, thereby infecting other cells and spreading the virus. Researchers from UMDNJ-Robert Wood Johnson Medical School and Rutgers, The State University of New Jersey, led by principal investigators Joseph Marcotrigiano and Smita Patel, show, for the first time, the structure of retinoic-acid-inducible gene-I, or RIG-I. RIG-I is a human protein that detects whether the RNA comes from a virus (viral RNA) and, if so, initiates an auto-immune response. Isolating the structure of RIG-I with RNA bound is the first step in developing broad-based therapies against viral infections.
The study, “Structural basis of RNA recognition and activation by innate immune receptor RIG-I,” was chosen for advanced online publication in Nature on September 25, 2011, and can be found online at: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10537.html.
“RIG-I is a very important protein that provides us with our first line of defense against viral infections, and prior to this work, there was little information on how RIG-I recognized viral RNAs,” said Smita Patel, PhD, professor of biochemistry at Robert Wood Johnson Medical School, whose lab specializes in the mechanics of biomolecules and the activity of enzymes. “A failure of RIG-I to identify viral RNA can lead to alterations of the cell, including cell death, inflammation, autoimmune diseases and cancer.”
“With the structure in hand, we will be able to design molecules to activate RIG-I or inhibit RIG-I depending on whether we want to fight viral infections or control inflammation,” said Joseph Marcotrigiano, PhD, assistant professor of chemistry and chemical biology at Rutgers University, whose lab specializes in determining structures of biomolecules including proteins, RNA, and DNA. Dr. Marcotrigiano also is a member of the Center for Advanced Biotechnology and Medicine, a joint institute of Robert Wood Johnson Medical School and Rutgers University.
RIG-I is a receptor that recognizes differences in molecular pathways in order to separate viral RNA from cellular RNA. Unlike DNA, RNA is normally made up of a single strand of nucleotides. However, viral RNA is double-stranded similar to the double-helical shape of DNA. Upon recognition of viral, double-stranded RNA, RIG-I initiates a signaling cascade to induce anti-immune and anti-inflammatory defenses within the cell.
The research team investigated the structure of RIG-I which is made up of a helicase enzyme, which works in conjunction with a repressor domain to recognize the viral RNA. This is the first step for sensing viruses and initiating synthesis of interferon molecules that “interfere” with viral infection, thereby preventing the spread of viral RNA. This work reveals at the atomic level the details of how RIG-I forms a capped ring around double-stranded RNA and how this structure formation activates RIG-I to initiate immune response.
“This work provides unprecedented insights on the molecular mechanism of viral RNA recognition by RIG-I,” said Barbara Gerratana, PhD, who oversees enzyme catalysis grants at the National Institute of General Medical Sciences of the National Institutes of Health. “As a result, we have a deeper understanding of how the human body fights viral infections and a structural basis for the development of new antiviral therapeutics.”
The research was supported with funding from the National Institutes of Health.
About UMDNJ-ROBERT WOOD JOHNSON MEDICAL SCHOOL
As one of the nation’s leading comprehensive medical schools, UMDNJ-Robert Wood Johnson Medical School is dedicated to the pursuit of excellence in education, research, health care delivery, and the promotion of community health. In cooperation with Robert Wood Johnson University Hospital, the medical school’s principal affiliate, they comprise New Jersey’s premier academic medical center. In addition, Robert Wood Johnson Medical School has 34 other hospital affiliates and ambulatory care sites throughout the region.
As one of the eight schools of the University of Medicine and Dentistry of New Jersey with 2,800 full-time and volunteer faculty, Robert Wood Johnson Medical School encompasses 22 basic science and clinical departments, hosts centers and institutes including The Cancer Institute of New Jersey, the Child Health Institute of New Jersey, the Center for Advanced Biotechnology and Medicine, the Environmental and Occupational Health Sciences Institute, and the Stem Cell Institute of New Jersey. The medical school maintains educational programs at the undergraduate, graduate and postgraduate levels for more than 1,500 students on its campuses in New Brunswick, Piscataway, and Camden, and provides continuing education courses for health care professionals and community education programs. To learn more about UMDNJ-Robert Wood Johnson Medical School, log on to rwjms.umdnj.edu. Find us online at www.Facebook.com/RWJMS and www.twitter.com/UMDNJ_RWJMS.
CONTACTS: Jennifer Forbes, UMDNJ-Robert Wood Johnson Medical School
Robin Lally, Rutgers University
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