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. 2020 Dec 4;10:609812. doi: 10.3389/fcimb.2020.609812

Figure 1.

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 IκB 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, IκB kinase subunit α; IKKb, IκB 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.