Invading pathogens may trigger overactivation of the innate immune system, which results in the release of large amounts of proinflammatory
cytokines (
cytokine storm) and leads to the development of
pulmonary edema, multiorgan failure, and
shock. PIAS1 is a multifunctional and potent anti-inflammatory
protein that negatively regulates several key inflammatory pathways such as
Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor κB (NF-κB). We discovered a
ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing
inflammation in an experimental
pneumonia model. We found that GSK3β phosphorylation of PIAS1 provided a phosphodegron for HECTD2 targeting. We also identified a mislocalized HECTD2 polymorphism, HECTD2(A19P), that was present in 8.5% of the population and functioned to reduce
inflammation. This polymorphism prevented HECTD2/PIAS1 nuclear interaction, thus preventing PIAS1 degradation. The HECTD2(A19P) polymorphism was also protective toward
acute respiratory distress syndrome (ARDS). We then developed a small-molecule inhibitor, BC-1382, that targeted HECTD2 and attenuated
lipopolysaccharide (LPS)- and Pseudomonas aeruginosa-induced
lung inflammation. These studies describe an unreported innate immune pathway and suggest that mutation or antagonism of the
E3 ligase HECTD2 results in reduced severity of
lung inflammation by selectively modulating the abundance of the anti-inflammatory
protein PIAS1.