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


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.

SUBMITTER: Rommereim LM 

PROVIDER: S-EPMC7853416 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Rommereim Leah M LM   Akhade Ajay Suresh AS   Dutta Bhaskar B   Hutcheon Carolyn C   Lounsbury Nicolas W NW   Rostomily Clifford C CC   Savan Ram R   Fraser Iain D C IDC   Germain Ronald N RN   Subramanian Naeha N  

Science signaling 20201208 661


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 l  ...[more]

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