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

Sci Signal. 2020 Dec 8;13(661):eaba3244. doi: 10.1126/scisignal.aba3244.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Regulation*
  • Humans
  • Inflammation / metabolism
  • Monocytes / metabolism*
  • Nod1 Signaling Adaptor Protein / biosynthesis*
  • Oncogene Proteins / biosynthesis*
  • Signal Transduction*
  • THP-1 Cells
  • Transcription, Genetic*

Substances

  • NOD1 protein, human
  • Nod1 Signaling Adaptor Protein
  • Oncogene Proteins