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 TNF alpha, IL-1 beta, 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 TNF alpha, IL-1 beta, or LPS plays a key role in initiating and/or perpetuating inflammation.

Automated summary

YAP9 is identified as an essential negative regulator of potent inflammatory stimuli like TNFα, IL-1β, and LPS, working in conjunction with A20 to suppress inflammatory responses. YAP9 and A20 utilize different structural domains to suppress inflammatory signaling, and synthetic peptides mimicking their functions can effectively suppress proinflammatory responses.