Editors' ChoiceImmunology

Limiting innate overreaction

Sci. Signal.  14 Jul 2015:
Vol. 8, Issue 385, pp. ec190
DOI: 10.1126/scisignal.aac9880

Pathogen infection triggers the innate immune system to release large amounts of proinflammatory cytokines that can have deadly consequences, such as pulmonary edema, shock, and organ failure. The E3 SUMO ligase PIAS1 [protein inhibitor of activated STAT1 (signal transducer and activator of transcription 1)] limits JAK (Janus kinase)–STAT and nuclear factor κB (NF-κB) signaling to prevent an excessive response. Coon et al. found that the E3 ubiquitin ligase HECTD2 ubiquitylated and mediated the degradation of PIAS1, thus contributing to lung inflammation in bacteria-infected mice. Overexpressing HECTD2 in HEK293T cells increased NF-κB reporter activity, either basally or in response to stimulation with lipopolysaccharide (LPS, a major component of gram-negative bacterial membranes) or the proinflammatory cytokines tumor necrosis factor or interferon-γ. Mapping analyses indicated a HECTD2-binding site in PIAS1 and a consensus motif for glycogen synthase kinase 3β (GSK3β)–specific phosphorylation within PIAS1. Indeed, in response to LPS, GSK3β phosphorylated PIAS1, creating a phosphodegron (phosphorylation-dependent degradation motif) that was recognized by HECTD2. Mutating this phosphorylation or binding site in PIAS1 prevented HECTD2 binding in vitro and increased PIAS1 stability when expressed in cells. Analysis of human single nucleotide polymorphism and population databases identified a naturally occurring polymorphism in HECTD2 (HECTD2-A19P) that was associated with decreased incidence of acute respiratory distress syndrome. In vitro, HECTD2-A19P polyubiquitylated PIAS1; however, in cells, HECTD2-A19P mislocalized to the cytosol, preventing its binding and ubiquitylation of PIAS1 in the nucleus. Mice either infected with lentivirus-encoded HECTD2-A19P or injected with a small-molecule inhibitor of HECTD2 (BC-1382) had increased abundance of PIAS1 and reduced lung inflammation in response to LPS injection or Pseudomonas aeruginosa infection. The findings suggest that some people are less susceptible to a hyperactive inflammatory response due to a polymorphism in HECTD2 and that pharmacologically targeting HECTD2 may have some therapeutic benefit to control the immune response in patients.

T. A. Coon, A. C. McKelvey, T. Lear, S. Rajbhandari, S. R. Dunn, W. Connelly, J. Y. Zhao, S. Han, Y. Liu, N. M. Weathington, B. J. McVerry, Y. Zhang, B. B. Chen, The proinflammatory role of HECTD2 in innate immunity and experimental lung injury. Sci. Transl. Med. 7, 295ra109 (2015). [Abstract]

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