Research ArticleImmunology

A small sustained increase in NOD1 abundance promotes ligand-independent inflammatory and oncogene transcriptional responses

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Science Signaling  08 Dec 2020:
Vol. 13, Issue 661, eaba3244
DOI: 10.1126/scisignal.aba3244

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A small NOD to big changes

NOD1 mediates proinflammatory and antimicrobial responses to pathogens. Infection with Helicobacter pylori, which is detected by NOD1, initiates inflammation that promotes gastric carcinogenesis. Rommereim et al. investigated how inflammatory and oncogenic transcriptional responses are affected by small changes in the abundance of NOD1. Suppression of the microRNA cluster miR-15b/16 increased the abundance of NOD1 by 1.2- to 1.3-fold and reduced the amount of ligand required to activate NOD1 in a monocytic cell line. NOD1-mediated transcriptional responses became ligand independent upon a 1.5-fold increase in NOD1 abundance. Both increases in NOD1 abundance resulted in disproportionately large increases in the expression of inflammatory genes and oncogenes. These data may explain why certain genetic variants in NOD1 and reduced miR-15b/16 abundance are associated with an increased risk for developing gastric cancer.


Small, genetically determined differences in transcription [expression quantitative trait loci (eQTLs)] are implicated in complex diseases through unknown molecular mechanisms. Here, we showed that a small, persistent increase in the abundance of the innate pathogen sensor NOD1 precipitated large changes in the transcriptional state of monocytes. A ~1.2- to 1.3-fold increase in NOD1 protein abundance resulting from loss of regulation by the microRNA cluster miR-15b/16 lowered the threshold for ligand-induced activation of the transcription factor NF-κB and the MAPK p38. An additional sustained increase in NOD1 abundance to 1.5-fold over basal amounts bypassed this low ligand concentration requirement, resulting in robust ligand-independent induction of proinflammatory genes and oncogenes. These findings reveal that tight regulation of NOD1 abundance prevents this sensor from exceeding a physiological switching checkpoint that promotes persistent inflammation and oncogene expression. Furthermore, our data provide insight into how a quantitatively small change in protein abundance can produce marked changes in cell state that can serve as the initiator of disease.

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