Nucleotide binding oligomerization domain (NOD)-like receptor (NLR) family member X1 (NLRX1) has been implicated in regulation of the Toll-like receptor (TLR)-mediated nuclear factor kappa-B (NF-kappa-B) signaling pathway. NLRX1 deficiency enhanced phosphorylation of catalytic subunits (CHUK and IKBKB) of the IkB kinase (IKK) complex and NF-kappa-B activation and led to elevated production of inflammatory cytokines in mouse cells in response to bacterial lipopolysaccharide (LPS, a TLR4 ligand) (Allen IC et al. 2011; Xia X et al. 2011; Ma D et al. 2019). NLRX1-knockdown mice showed enhanced susceptibility to LPS-induced septic shock thus further confirming that NLRX1 functions as a negative regulator of TLR signaling in vivo (Xia X et al. 2011). NLRX1 was shown to interact with TRAF6 (Allen et al. 2011; Xia X et al. 2011) and the IKK complex (CHUK:IKBKB:IKBKG) (Xia X et al. 2011) in human and mouse cells. Specifically, in unstimulated cells, NLRX1 was shown to associate with TRAF6 (Xia X et al. 2011). Upon stimulation with LPS, NLRX1 is thought to undergo K63-linked polyubiquitination. Although TRAF6 possesses E3 ubiquitin ligase activity, the TRAF6 deficiency did not affect NLRX1 ubiquitination in mouse embryonic fibroblast (MEF) (Xia X et al. 2011). Further studies are required to identify E3 ubiquitin ligase which is responsible for the ubiquitination of NLRX1. Ubiquitinated NLRX1 then binds to the IKK complex, blocking phosphorylation of the catalytic subunits CHUK (IKBKA) and IKBKB (Xia X et al. 2011). Mutagenesis studies showed that the C-terminal leucine-rich repeat (LRR) domain of NLRX1 binds to the kinase domain of IKBKB (Xia X et al. 2011).

The regulatory effects of NLRX1 are highly cell type specific (reviewed in Fekete T et al. 2021). As a regulator of inflammation, NLRX1 has been implicated in the pathology of diverse diseases (reviewed in Pickering RJ & Booty LM 2021).

This Reactome event shows interaction between NLRX1 and the IKK complex.