- Open Access
New tricks for old NODs
© BioMed Central Ltd 2008
- Published: 25 April 2008
Recent work has identified the human NOD-like receptor NLRX1 as a negative regulator of intracellular signaling leading to type I interferon production. Here we discuss these findings and the questions and implications they raise regarding the function of NOD-like receptors in the antiviral response.
- Antiviral Response
- Interferon Response
- Interferon Signaling
- Interferon Production
- Card Domain
Upon infection with a pathogen, the host cell must recognize its presence, communicate this to neighboring cells and tissues and initiate a biological response to limit the spread of infection and clear the pathogen. Recognition of invading microbes proceeds via specialized intracellular and extracellular proteins termed pattern recognition receptors (PRRs), which recognize conserved molecular motifs found on pathogens, known as pathogen-associated molecular patterns (PAMPs). Recognition of PAMPs by PRRs leads to the activation of downstream transcription factors, resulting in induction of programs of host defense gene expression designed to effect immunity to the pathogen. In the innate immune response to viruses, the genes activated include those for the type I interferons - the primary cytokines mediating the innate response to viral infection. In mammals, these comprise IFNβ, 13 IFNαs and the more recently discovered IFNω. Type I interferons signal via the IFNα/β receptor to induce further sets of genes that regulate cellular metabolic processes, intracellular nutrient availability, apoptotic responses and direct elimination of the pathogen .
In a paper recently published in Nature, Moore et al.  have shown that these MAVS-mediated pathways can be inhibited by the action of an intracellular NOD-like receptor (NLR), the protein NLRX1, indicating that members of this ancient family of pathogen sensors can evolve to acquire new regulatory roles in mammalian host defense.
This study leaves a number of interesting questions still open. In particular, the precise mechanism by which NLRX1 inhibits MAVS-mediated signaling is not clear. The data of Moore et al.  suggest that MAVS and NLRX1 may interact constitutively, and that NLRX1 can inhibit the interaction between RIG-I and MAVS. While this suggests that NLRX1 interferes with the interaction between RIG-I and MAVS, it follows that this interference must be overcome to allow for proper interferon signaling. Perhaps activated RIG-I has a higher affinity for the CARD domain of MAVS than does NLRX1, thus titrating out the NLRX1-MAVS interaction and allowing interferon signaling. Alternatively, the LRR domain of NLRX1 might pick up 'danger' signals generated by viral infection in a fashion similar to NALP3, thus releasing inhibition by making the NLRX1-MAVS interaction less favorable. Furthermore, as NLRX1 can inhibit interferon signaling induced by overexpressed MAVS in the absence of virus, the role of NLRX1 in blocking the interaction between MAVS and downstream interferon signaling components should be addressed.
An interesting, although elusive, aspect of the MAVS-NLRX1 story is the function of mitochondrial localization for these proteins. In both cases, loss of mitochondrial localization as a result of experimental manipulation or cleavage from the membrane by viral proteases, as in the case of deactivation of MAVS by the hepatitis C virus protease NS3/4A, completely destroys the function of these proteins [5, 6, 13]. It may be, as Moore et al.  suggest, that the mitochondrion provides a useful platform on which sufficient concentrations of signaling elements can be marshaled to effect downstream signaling processes. Given the key role of mitochondria in apoptotic and metabolic functions and the intimate relationship of these processes with viral infection, it is no small leap to reason that MAVS and NLRX1 may serve as an interface between them. In addition, as with MAVS, cleavage of NLRX1 from the mitochondrial surface by endogenous or viral proteases might serve as a mechanism for damping NLRX1-mediated inhibition of interferon production.
It was previously shown by the same group that Monarch-1/NLRP12, a soluble NLR family member, can inhibit activation of the noncanonical NF-κB pathway in response to CD40 stimulation [15, 20]. Thus, Monarch-1, and now NLRX1, represent what is probably a recent evolutionary retooling of some NLRs from inflammatory or cell-death mediators to checkpoint proteins designed to regulate immunological signaling processes. Given the fact that NLRs essentially act as molecular switches in response to stimuli sensed via their LRRs, it seems logical that they might be adapted to act as negative regulators that can be inducibly released or activated in the appropriate conditions. Indeed, the concept of such switches is recapitulated in many other biological systems: the Ras family of GTPases is but one example.
A persistent question and the genesis of significant debate within the innate immunity field is the mechanism by which these NLR switches are activated. Taking a precedent from the study of Toll-like receptors, some of whose LRR domains have been shown to physically interact with ligands, the conventional wisdom has been that NLRs also respond to specific PAMPs. Indeed, NOD1 and NOD2 have been shown to respond via their LRRs to bacterial peptidoglycans, although convincing biochemical evidence showing a direct interaction is lacking [16, 17]. However, several studies showing that NALP3-mediated inflammasome formation is induced by a wide range of stimuli, from uric acid crystals to double-stranded RNA to ionophore stimulation, has thrown this conventional wisdom into disfavor [18, 19, 21–23]. The prevailing alternative hypothesis is that NLRs respond to nonspecific cellular perturbations or danger signals rather than discrete ligands. Thus, it will be important to determine what, if any, signal might be sensed via the LRRs of NLRX1. Given that NALP3 also responds to viral infection, it will be interesting to determine whether these two NLRs might respond to the same signal upon viral infection.
It is clear that there are numerous unanswered questions on the biology of NLRX1 in the interferon response as well as on the biology of NLRs in general. Although the interferon response might be considered an evolutionary contemporary of NLRs, the findings of Moore et al.  clearly suggest that the members of this family of proteins, and NLRX1 in particular, have evolved to play significant roles in directly regulating pathways that control more modern biological functions.
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