NLRX1 Is a Multifaceted and Enigmatic Regulator of Immune System Function

Abstract

Over the last decade, significant progress has been achieved in defining mechanisms underlying NLR regulation of immune system function. However, several NLR family members continue to defy our best attempts at characterization and routinely exhibit confounding data. This is particularly true for NLR family members that regulate signaling associated with the activation of other pattern recognition receptors. NLRX1 is a member of this NLR sub-group and acts as an enigmatic regulator of immune system function. NLRX1 has been shown to negatively regulate type-I interferon, attenuate pro-inflammatory NF-κB signaling, promote reactive oxygen species production, and modulate autophagy, cell death, and proliferation. However, the mechanism/s associated with NLRX1 modulation of these pathways is not fully understood and there are inconsistencies within the field. Likewise, it is highly likely that the full repertoire of biological functions impacted by NLRX1 are yet to be defined. Recent mouse studies have shown that NLRX1 significantly impacts a multitude of diseases, including cancer, virus infection, osteoarthritis, traumatic brain injury, and inflammatory bowel disease. Thus, it is essential that the underlying mechanism associated with NLRX1 function in each of these diseases be robustly defined. Here, we summarize the current progress in understanding mechanisms associated with NLRX1 function. We also offer insight into both unique and overlapping mechanisms regulated by NLRX1 that likely contribute to disease pathobiology. Ultimately, we believe that an improved understanding of NLRX1 will result in better defined mechanisms associated with immune system attenuation and the resolution of inflammation in a myriad of diseases.

Focusing on the Cell Type Specific Regulatory Actions of NLRX1

“…The abovementioned studies and further examples have already been nicely reviewed in a previous publication [ 17 ]. Most of the clinical studies do not reveal details about the cell type specific regulation of NLRX1; however, these studies have a very important role in confirming the in vivo regulatory functions of NLRX1, which have been addressed only in in vitro or ex vivo models so far.…”

“…Furthermore, NLRX1 has also been found to contribute to metabolic disorders. The importance of NLRX1 in inflammatory, metabolic and oncological diseases have been already addressed in previous and recent reviews [ 17 , 18 ]. Since NLRX1 contributes to a multitude of diseases, targeting NLRX1 could offer promising treatment strategies in immune cell-, or non-immune cell-mediated diseases [ 18 ].…”

Understanding the complexities of SARS-CoV2 infection and its immunology: A road to immune-based therapeutics

“…Hence, the SARS-CoV2 virus hijacks the MHC-1-dependent Ag presentation of the host to protect from itself from the direct killing by CD8 + T cells. The SARS-CoV2 ORF9c interacts with NLRX1 [a NOD-like receptor family member, which negatively regulates TLR signaling-induced NF-κB activation via interacting with TRAF6 or IκB kinase (IKK)], impacts RLR-mediated antiviral immune response, reactive oxygen species generation, and NLRP3 inflammasome activation, thus the release of IL-1β to modulate NF-κB signaling and IκB kinase ( Table 1 ) [316] , [328] , [329] , [330] , [331] . Hence, SARS-CoV2 infection hijacks the cytosolic cellular mechanisms responsible for generating potent type 1 IFNs through cGAS, RLR, and TLR-based mechanisms required to clear the virus and induced antiviral immune response in the adjacent cells.…”

NLR in eXile: Emerging roles of NLRX1 in immunity and human disease

“…NLRX1 comprises two of the three typical NLR domains, a central NACHT domain and a carboxy‐terminus LRR domain but lacks a recognizable N‐terminal effector domain found in other NLRs (Figure 1). Instead, NLRX1 contains an unconventional N‐terminal domain, that has no current assigned function, giving rise to the ‘X’ in the nomenclature 6 . However, unique to the NLR family, NLRX1 possesses a mitochondrial targeting sequence (MTS) encoded in the first 39 amino acids of the protein 7 .…”