A small sustained increase in NOD1 abundance promotes ligand-independent inflammatory and oncogene transcriptional responses.
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.
Institute for Systems Biology
Rommereim, Leah M; Akhade, Ajay Suresh; Dutta, Bhaskar; Hutcheon, Carolyn; Lounsbury, Nicolas W; Rostomily, Clifford C; Savan, Ram; Fraser, Iain D C; Germain, Ronald N; and Subramanian, Naeha, "A small sustained increase in NOD1 abundance promotes ligand-independent inflammatory and oncogene transcriptional responses." (2020). Articles, Abstracts, and Reports. 4257.