Yeretssian et al. reply

Abstract

Replying to U. Nachbur, J. E. Vince, L. A. O'Reilly, A. Strasser & J. Silke Nature 488, 10.1038/nature11366 (2012).

Nucleotide-binding and oligomerization domain (NOD) receptors are cytosolic sensors of microbe-associated molecular patterns (MAMPs). Like other members of the BCL2 family of proteins (such as BCL2 and BCL-X_L¹), BID has a role in inflammation and innate immunity^2,3. Its association with the NOD signallosome showed it to be an important player in the pathway. Furthermore, a recent report demonstrated unequivocal and direct binding of BID to purified NOD1 protein⁴. Although Nachbur et al.⁵ question whether BID is essential for NOD signalling, they show no clear evidence to the contrary. Instead, they provided three data sets, and an analysis of these data sets is presented in Fig. 1 and Appendix Fig. 1 (ref. 5). Although there was considerable variability in the results from these independently performed experiments (also apparent in the data presented in their Comment), overall the data support the findings in our Letter⁶ that BID contributes to the NOD-mediated response. A challenge to our conclusions was based on the claim that BID deficiency does not affect NOD signalling. Data in Appendix Fig. 1a and b (ref. 5) support our conclusions and show a role for BID in NF-κB activation (decreased p65 phosphorylation). By contrast, a third set of immunoblots shows the opposite effect, in which BID seems to be a negative regulator of NF-κB signalling (increased p65 phosphorylation in Bid^−/− cells; Fig. 1 from ref. 5). The basis for these incoherent and non-reproducible results is unclear but suggests technical caveats. For instance, it is surprising to see p65 phosphorylation in Ripk2^−/− cells (Fig. 1c in ref. 5).