title: 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 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.
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Coon
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Alison C
authors.initials: AC
authors.lastname: McKelvey
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Lear
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Shristi
authors.initials: S
authors.lastname: Rajbhandari
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Dunn
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: William
authors.initials: W
authors.lastname: Connelly
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Joe Y
authors.initials: JY
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: SeungHye
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Nathaniel M
authors.initials: NM
authors.lastname: Weathington
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: McVerry
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh, Pittsburgh, PA 15213, USA. Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA. chenb@upmc.edu.
authors.forename: Bill B
authors.initials: BB
authors.lastname: Chen
mesh_terms: D000818:Animals; D055785:Gene Knockdown Techniques; D007113:Immunity, Innate / Q000502:physiology*; D007249:Inflammation / Q000503:physiopathology*; D055370:Lung Injury / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology*; D051379:Mice; D010766:Phosphorylation; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism; D011549:Pseudomonas / Q000472:pathogenicity; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: C494211:Pias1 protein, mouse; D050828:Protein Inhibitors of Activated STAT; C000607402:HECTD2 protein, mouse; D044767:Ubiquitin-Protein Ligases