A small sustained increase in NOD1 abundance promotes ligand-independent inflammatory and oncogene transcriptional responses.
Sci Signal
; 13(661)2020 12 08.
Article
en En
| MEDLINE
| ID: mdl-33293463
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transcripción Genética
/
Monocitos
/
Transducción de Señal
/
Regulación de la Expresión Génica
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Proteínas Oncogénicas
/
Proteína Adaptadora de Señalización NOD1
Límite:
Humans
Idioma:
En
Revista:
Sci Signal
Asunto de la revista:
CIENCIA
/
FISIOLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos