Survey Activation and regulation of pathogen sensor RIG-I Jenish R. Patel a,c, *, Adolfo Garcı ´a-Sastre a,b,c a Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA b Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA c Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513 2. Nucleic acid sensors in innate immunity against pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514 3. Establishment of RIG-I as a pathogen sensor in the type-I interferon pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 4. Identification of 5 0 -ppp as the primary ligand of RIG-I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 5. Role for RIG-I in the antimicrobial response to viruses and bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516 6. Structure of RIG-I. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518 7. Mechanism of activation of RIG-I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519 8. Regulating the function of RIG-I in cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519 9. Pathogen antagonism of the RIG-I sensing pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520 10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521 1. Introduction Recognition of a pathogen in an infected host relies on a distinctive set of cellular sensors or pattern recognition receptors (PRR) that detect specific pathogen-associated molecular patterns (PAMP). Such detection then leads to a generalized antimicrobial response to eliminate the pathogen at the site of infection. Importantly, this process also plays a critical role in the proper initiation of adaptive immunity by production of cytokines and chemokines that activate inflammatory pathways and recruit immune cells such as dendritic cells, which then carry antigens to lymphoid organs to activate the effector lymphocyte responses. This ensuing specialized response not only involves direct killing of infected cells but also production of antibodies specific to the pathogen, culminating in the development of immunological memory. PRRs can be found in most cell types, including non- immune cells such as cells of the epithelia and immune cells such as macrophages. The innate immune response to a pathogen is initiated by the production of type-I interferons and proinflammatory cytokines. Type I interferons bind and stimulate the interferon a/b receptor Cytokine & Growth Factor Reviews 25 (2014) 513–523 A R T I C L E I N F O Article history: Available online 23 August 2014 Keywords: Type I interferon Antiviral response Virus Innate immunity RIG-I-like receptors A B S T R A C T Cells are equipped with a large set of pattern recognition receptors or sensors that detect foreign molecules such as pathogenic nucleic acids and initiate proinflammatory and antimicrobial innate immune responses. RIG-I is a cytosolic sensor that detects 5 0 -triphosphate double-stranded RNAs produced during infection. RIG-I is responsible for mounting an antimicrobial response against a variety of viruses and intracellular bacteria. RIG-I contains an intricate structural architecture that allows for efficient signaling downstream in the pathway and autoregulation. The RIG-I-mediated antimicrobial pathway is highly regulated in cells requiring various cofactors, negative regulators, and posttransla- tional modifications. Modulation of RIG-I and RIG-I-mediated signaling in cells by pathogens to evade recognition and activation of the antimicrobial pathway highlights the essential nature of RIG-I in the innate immune response. ß 2014 Elsevier Ltd. All rights reserved. * Corresponding author at: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Tel.: +1 6784536474. E-mail addresses: jenish.patel@mssm.edu, jenishpatel5@gmail.com (J.R. Patel). Contents lists available at ScienceDirect Cytokine & Growth Factor Reviews jo ur n al ho mep ag e: www .elsevier .c om /loc ate/c yto g fr http://dx.doi.org/10.1016/j.cytogfr.2014.08.005 1359-6101/ß 2014 Elsevier Ltd. All rights reserved.