Nucleotide oligomerization domain-2 interacts with 2′-5′-oligoadenylate synthetase type 2 and enhances RNase-L function in THP-1 cells

Abstract

Nucleotide-binding and oligomerization domain 2 (NOD2) is an intracellular a protein involved in innate immunity and linked to chronic inflammatory diseases in humans. Further characterization of the full spectrum of proteins capable of binding to NOD2 may provide new insights into its normal functioning as well as the mechanisms by which mutated forms cause disease. Using a proteomics approach to study human THP-1 cells, we have identified 2’-5’-oligoadenylate synthetase type 2 (OAS2), a dsRNA binding protein involved in the pathway that activates RNase-L, as a new binding partner for NOD2. The interaction was confirmed using over-expression of OAS2 and NOD2 in HEK cells. Further confirmation was obtained by detecting NOD2 in immunoprecipitates of endogenous OAS2 in THP-1 cells. Finally, over-expression of NOD2 in THP-1 cells led to enhanced RNase-L activity in cells treated with poly(I:C), a mimic of double-stranded RNA virus infection. These data indicate connectivity in pathways involved in innate immunity to bacteria and viruses and suggest a regulatory role whereby NOD2 enhances the function of RNase-L.

The protein Nod2: An innate receptor more complex than previously assumed

“…Nod2 was shown to interact with OAS2 and enhance RNAse-L activity in cells treated with poly(I:C), a mimic of double-stranded RNA virus infection [60]. These results suggest that Nod2 would be not only able to mediate IFN-b production after infection by ssRNA virus but could be also involved through an indirect mechanism in RLRs-dependent type1 interferons expression after dsRNA virus infection.…”

Characterization of the termini of the West Nile virus genome and their interactions with the small isoform of the 2′ 5′-oligoadenylate synthetase family

“…Expression levels of cathepsin, an important enzyme in lysosomes that plays a major role in lysosomal degradation of macrophage--internalized foreign substances of bacterial and other pathogenic origin, has been shown to be regulated by RNase L [250--252]. An enhanced antibacterial response could be possible through higher RNase L activity via the interaction of OAS2 with NOD2 in the presence of poly I:C (an synthetic dsRNA activator of OAS and IFN response) [253].…”

Blau syndrome revisited

“…Furthermore, a new role of NOD2 as a viral pattern recognition receptor is emerging. The dsRNA binding protein, OAS2, was recently shown to interact directly with NOD2 in response to dsRNA stimulation, resulting in enhanced RNAse-L activity [44]. Sabbah et al [45] described the interaction between NOD2 and the adapter protein mitochondrial antiviral signaling protein in response to ssRNA which lead to an activation of IRF3 resulting in production of IFNg.…”