YAP9/A20 Complex Suppresses Proinflammatory Responses and Provides Novel Anti-inflammatory Therapeutic Potentials

Innate anti-inflammatory mechanisms are essential for immune homeostasis and can present opportunities to intervene inflammatory diseases. In this report, we found that YAP isoform 9 (YAP9) is an essential negative regulator of the potent inflammatory stimuli such as TNFa, IL-1ß, and LPS. YAP9 constitutively interacts with another anti-inflammatory regulator A20 (TNFAIP3) to suppress inflammatory responses, but A20 and YAP can function only in the presence of the other. YAP9 uses a short stretch of amino acids in the proline-rich domain (PRD) and transactivation domain (TAD) suppress the inflammatory signaling while A20 mainly uses the zinc finger domain 7 (ZF7). Cell-penetrating synthetic PRD, TAD, and ZF7 peptides act as YAP9 and A20 mimetics respectively to suppress the proinflammatory responses at the cellular level and in mice. Our data uncover a novel anti-inflammatory axis and anti-inflammatory agents that can be developed to treat acute or chronic conditions where TNFa, IL-1ß, or LPS plays a key role in initiating and/or perpetuating inflammation. Overall design: To investigate the effect of skeleton stress' effect on cell gene expression, FLS were cultured in plastic tissue culture plate (2D) for 2 days or Vitrogel for 7 days and stimulated with TNFa (1ng/ml) for 2h in duplicates. Total RNAs were collected and subjected to RNAseq.