YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes
Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed....
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-06-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/13/6649 |
| Summary: | Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed. This study examined the expression pattern of <i>Tlr1</i>, <i>Tlr2</i>, <i>Tlr3</i>, <i>Tlr4</i>, <i>Tlr5</i>, <i>Tlr6</i>, <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i> in normal and disease-stressed mouse hearts. Our results demonstrated that the expression levels of cardiac <i>Tlr3</i>, <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i> increased with age between neonatal and adult developmental stages, whereas the expression of <i>Tlr5</i> decreased with age. Furthermore, pathological stress increased the expression levels of <i>Tlr2</i>, <i>Tlr4</i>, <i>Tlr5</i>, <i>Tlr7</i>, <i>Tlr8</i>, and <i>Tlr9</i>. Hippo-YAP signaling is essential for heart development and homeostasis maintenance, and YAP/TEAD1 complex is the terminal effector of this pathway. Here we found that TEAD1 directly bound genomic regions adjacent to <i>Tlr1</i>, <i>Tlr2</i>, <i>Tlr3</i>, <i>Tlr4</i>, <i>Tlr5</i>, <i>Tlr6</i>, <i>Tlr7</i>, and <i>Tlr9</i>. In vitro, luciferase reporter data suggest that YAP/TEAD1 repression of <i>Tlr4</i> depends on a conserved TEAD1 binding motif near <i>Tlr4</i> transcription start site. In vivo, cardiomyocyte-specific YAP depletion increased the expression of most examined TLR genes, activated the synthesis of pro-inflammatory cytokines, and predisposed the heart to lipopolysaccharide stress. In conclusion, our data indicate that the expression of cardiac TLR genes is associated with age and activated by pathological stress and suggest that YAP/TEAD1 complex is a default repressor of cardiac TLR genes. |
|---|---|
| ISSN: | 1661-6596 1422-0067 |