The proinflammatory role of HECTD2 in innate immunity and experimental lung injury

Abstract

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 GSK3b phosphorylation of PIAS1 provided a phosphodegron for HECTD2 targeting. We also identified a mislocalized HECTD2 polymorphism, HECTD2A19P, 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 HECTD2A19P 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.

Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication

“…S4 A and B). HECTD2 is implicated in regulating PIAS1 (32) and as a candidate susceptibility gene in Alzheimer's disease and Creutzfeldt-Jakob disease (33,34). Consistent with the result of the siRNA screen, HECTD2 coimmunoprecipitates LCA but not LCE (Fig.…”

B Cell Receptor Activation and Chemical Induction Trigger Caspase-Mediated Cleavage of PIAS1 to Facilitate Epstein-Barr Virus Reactivation

“…Although PIAS1 protein stability has been shown to be regulated by the ubiquitin-proteasome pathway and the E3 ubiquitin ligases SIAH1/SIAH2, HECTD2 and adaptor protein necdin are known to promote PIAS1 ubiquitination and subsequent degradation (Coon et al, 2015; Depaux et al, 2007; Gur et al, 2014), our study reveals a surprising regulation of PIAS1 by apoptotic caspases. We further provided evidence that caspase-dependent cleavage of PIAS1 plays a key role in EBV lytic replication (Figure 6).…”

RING finger E3 ligase PPP1R11 regulates TLR2 signaling and innate immunity

“…To investigate the in vivo relevance of the PPP1R11/TLR2 pathway, we assayed white blood cell (WBC) pellets for PPP1R11 and TLR2 expression in control and S. aureus -infected patients from our Acute Lung Injury Registry and Biospecimen Repository (Coon et al, 2015). Control patients were mechanically ventilated patients intubated for airway protection without clinical evidence of or risk factors for ARDS (Acute Respiratory Distress Syndrome), while S. aureus -infected patients had evidence of S. aureus in tracheal aspirates, blood, or both, and had evidence of or risk factors for ARDS.…”

“…for 144 hr before the administration of S. aureus (strain 29213, 2.5*107-108 CFU/mouse, i.t.) for 18 hr, after which animals were euthanized and assayed for BAL protein, cell count, cytokines, lung infiltrates, and tissue bacterial count (Coon et al, 2015; Zhao et al, 2012; Chen et al, 2013; Mallampalli et al, 2013)…”