Promyelocytic leukemia protein interacts with the apoptosis-associated speck-like protein to limit inflammasome activation

  • J Biol Chem. 2014 Mar 7;289(10):6429-6437. doi: 10.1074/jbc.M113.539692.
Jennifer K Dowling  1 ,  Christine E Becker  1 ,  Nollaig M Bourke  2 ,  Sinead C Corr  1 ,  Dympna J Connolly  1 ,  Susan R Quinn  1 ,  Paolo P Pandolfi  3 ,  Ashley Mansell  2 ,  Luke A J O'Neill  4
Affiliations
  • 1. Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, Pearse Street, Dublin 2, Ireland.
  • 2. Centre for Innate Immunity and Infectious Disease, MIMR-PHI Institute of Medical Research, Monash University, Clayton, Victoria 3168, Australia.
  • 3. Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 01605.
  • 4. Trinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, Pearse Street, Dublin 2, Ireland. Electronic address: [email protected].
PMID: 24407287 DOI: 10.1074/jbc.M113.539692
Abstract

The apoptosis-associated speck-like protein containing a caspase-activating recruitment domain (ASC) is an essential component of several inflammasomes, multiprotein complexes that regulate Caspase-1 activation and inflammation. We report here an interaction between promyelocytic leukemia protein (PML) and ASC. We observed enhanced formation of ASC dimers in PML-deficient macrophages. These macrophages also display enhanced levels of ASC in the cytosol. Furthermore, IL-1β production was markedly enhanced in these macrophages in response to both NLRP3 and AIM2 inflammasome activation and following bone marrow-derived macrophage Infection with herpes simplex virus-1 (HSV-1) and Salmonella typhimurium. Collectively, our data indicate that PML limits ASC function, retaining ASC in the nucleus.

Keywords
Cancer; Cytokine; Inflammasome; Inflammation; Innate Immunity; Nod-like Receptors (NLR).