NLRX1 is a regulator of mitochondrial antiviral immunity

Nature 451, 573-577 (2008)

Speaker : 阮馨怡                                                  Time : 14:00~15:00, Mar.26, 2008

Commentator : 劉校生 老師                                Place: Room 601

Abstract:

Three families of pathogen sensors — TLRs (Toll-like receptors), NLRs (Nod-like receptors) and RLRs (RIG-like receptors) sense microbial structures and mediate innate immune response. While TLRs recognize extracellular foreign organisms, NLRs and RLRs function as cytoplasmicsurveillance molecules that survey the cytoplasm for intracellular invaders.¹ When viral dsRNA binds to RIG-I, which in turn activates downstream adaptor protein MAVS (mitochondrial antiviral signalingprotein) to promote NF-κB (nuclear factor-kappa B) and IRF3 (interferon regulatory factor 3) response, leading to interferon-β transcription.² A novel mitochondrial NLR identified NLRX1 localizes at the mitochondrial outer membrane and antagonizes the immune response via the interaction with MAVS. In this study, the authors discovered that NLRX1 expression blocked MAVS-associated activation of NF-κB and IFN-β. During Sendai virus infection, the expression of NLRX1 would attenuate MAVS and Sendai-virus-induced IRF3 dimer formation. These data showed that Sendai virus infection enhanced the association of MAVS and RIG-I, and NLRX1 blocked this interaction lead to reduce MAVS-mediated IRF3 signalling. Furthermore, the authors demonstrated the depletion of endogenous NLRX1 with siRNA could restore type I IFN production, NF-κB activity and decrease viral replication. As RIG-I and NLRX1 both bind to the CARD(caspaseactivating and recruitment domain) domain of MAVS, indicating that NLRX1 and RIG-I may compete for binding to MAVS, although with opposing effects. This report showed NLRX1 is such a brake. NLRX1 act as a modulator of the immune response could be important for regulating IFN-β signaling, enabling precise control of the antiviral response.

References:

1. Emma M. Creagh and Luke A.J. O’Neill. TLRs, NLRs and RLRs: a trinity of pathogen sensors that co-operate in innate immunity. Trends Immunol. 27, 352-357 (2006).

2. Etienne Meylan, Ju¨rg Tschopp & Michael Karin. Intracellular pattern recognition receptors in the host response. Nat. Rev. 442, 39-44(2006).