Behind the Scenes: Nod-Like Receptor X1 Controls Inflammation and Metabolism

Abstract

Regulatory Nod-like receptors (NLRs) are a subgroup of the cytosolic NLR family of pathogen recognition receptors (PRRs). These receptors can tune the innate immune responses triggered by the activation of other PRRs by either augmenting or attenuating the activated pro-inflammatory signaling cascades. Nod-like receptor X1 (NLRX1) is the only known mitochondria-associated negative regulatory NLR. NLRX1 attenuates several inflammatory pathways and modulates cellular processes such as autophagy and mitochondrial function following infection or injury. Using both in vitro expression and in vivo experimental models, NLRX1 is extensively described in the context of anti-viral signaling and host-defense against invading pathogens. More recently, NLRX1 has also gained interest in the field of cancer and metabolism where NLRX1 functions to attenuate overzealous inflammation in various inflammatory and autoimmune diseases. However, the exact function of this novel receptor is still under debate and many, often contradictory, mechanisms of action together with cellular localizations have been proposed. Thus, a better understanding of the underlying mechanism is crucial for future research and development of novel therapeutical approaches. Here, we summarize the current findings on NLRX1 and discuss its role in both infectious and inflammatory context.

Keywords: infection; inflammation; metabolism; mitochondria; nod-like receptor X1.

Figure 1

NLRX1 regulates multiple cellular pathways to control inflammation in response to infection and stress. NLRX1 is addressed to the mitochondria via the N-terminal mitochondrial targeting sequence (MTS). Studies identified a C-terminal RNA-binding element and coherently, NLRX1 plays a role in anti-viral signaling by inhibition of type I interferon signaling through direct interaction with the outer membrane (OM) mitochondrial anti-viral signaling protein (MAVS). However, some studies describe that NLRX1 attenuates viral replication in the cytoplasm via a MAVS-independent mechanism, potentially through binding of stimulator of interferon genes (STING). Inhibition of type I IFN signalling following virus infection is associated to enhanced autophagy and mitophagy through association of NLRX1 with either the Tu translation elongation factor (TUFM) or GTPase dynamin-related protein 1 (DRP1). Similarly, NLRX1 is associated to enhanced mitochondrial reactive oxygen species (mtROS) production and decreased oxygen consumption and mitochondrial oxidative phosphorylation (OXPHOS) following virus or bacterial infection through interaction with the mitochondrial protein ubiquinol-cytochrome c reductase core protein II (UQCRC2). Growing interest has been attributed to the role of NLRX1 as a modulator between inflammation and metabolism. Following cellular stress, NLRX1 inhibits activation of NF-_κB through its direct interaction with TRAF6 or I_κB kinase (IKK) complex. NLRX1 may indeed play a more general role in the maintenance of mitochondrial physiology and cellular homeostasis. AP-1, activator protein 1; cGAS, cyclic GMP-AMP synthase; ER, endoplasmic reticulum; FASTKD5, FAST kinase domain-containing protein 5; IKKa, I_κB kinase subunit α; IKKb, I_κB kinase subunit β; IM, inner membrane; IRF3, interferon regulatory factor 3; JNK, c-Jun N-terminal kinase; LC3, microtubule-associated protein 1A/1B-light chain 3; LIR, LC3-interacting domain; LRR, leucine rich repeat domain; MAPK, mitogen-activated protein kinase; NACHT, central nucleotide-binding oligomerization domain; NEMO, NF-_κB essential modulator; NF-_κB, nuclear factor kappa-light-chain-enhancer of activated B cells; p38, p38 mitogen activated protein kinase; RIG-I, retinoic acid-inducible gene I; TAK1, transforming growth factor-β activated kinase-1; TBK1, TANK-binding kinase 1; TRAF6, TNF receptor-associated factor 6.

Figure 2

NLRX1 modulates innate immunity and inflammation. Multiple mechanisms of action and direct interacting partners are proposed in different experimental models. The N-terminal central nucleotide-binding domain (NACHT) of NLRX1 plays a role in attenuating MAVS-dependent anti-viral signalling by inhibiting the type I interferon (IFN) response against both ssRNA and dsRNA viruses. In addition, the NACHT domain was necessary to inhibit invasion and autophagosome formation upon Streptococcus A infection. Multiple functions are proposed to depend on the C-terminal leucine rich repeat (LRR). LRR was shown to directly bind a viral RNA polymerase Nsp9 of porcine reproductive and respiratory syndrome virus-2 (PRRSV2) to limit virus replication, or to bind LC3 to induce Listeria monocytogenes-dependent mitophagy, or to induce mtROS upon RNA stimulation. The LRR also limited inflammation in both infectious and inflammatory disease models. Many binding partners have been proposed using the endogenous protein. NLRX1 could play a role in modulating type I IFN signalling, NF-_KB pathway, autophagy and several mitochondrial functions. Thus, a consensus regarding the exact mechanism of action of NLRX1 still requires further investigation. DRP1, GTPase dynamin-related protein 1; FASTKD5, FAST kinase domain-containing protein 5; HPV, human papillomavirus; IKK, I_κB kinase; LC3, microtubule-associated protein 1A/1B-light chain 3; LPS, lipopolysaccharide; MTS, mitochondrial targeting sequence; MAVS, mitochondrial anti-viral signaling protein; NF-_κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; Nsp9, a viral non-structural protein 9; PB1-F2, influenza virus protein PB1-F2; PCBC2, poly(rC) binding protein 2; ROS, reactive oxygen species; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1; TRAF6, TNF receptor-associated factor 6, TUFM, Tu translation elongation factor; UQCRC2, ubiquinol-cytochrome c reductase core protein II; UVRAG, UV irradiation resistance-associated gene.