Journal
MOLECULAR CELL
Volume 28, Issue 2, Pages 214-227Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2007.08.029
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Funding
- NCI NIH HHS [P01 CA078890, CA78890, T32-CA09678, P01 CA078890-08] Funding Source: Medline
- NIA NIH HHS [AG14357, R01 AG014357, R01 AG014357-10] Funding Source: Medline
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The molecular mechanism by which mutations in the cytos keleton-organizing protein PSTPIP1 cause the autoinflammatory PAPA syndrome is still elusive. Here, we demonstrate that PSTPIP1 requires the familial Mediterranean fever protein pyrin to assemble the ASC pyroptosome, a molecular platform that recruits and activates caspase-1. We provide evidence that pyrin is a cytosolic receptor for PSTPIP1. Pyrin exists as a homotrimer in an autoinhibited state due to intramolecular interactions between its pyrin domain (PYD) and B-box. Ligation by PSTPIP1, which is also a homotrimer, activates pyrin by unmasking its PYD, thereby allowing it to interact with ASC and facilitate ASC oligomerization into an active ASC pyroptosome. Because of their high binding affinity to pyrin's B-box PAPA-associated PSTPIP1 mutants were found to be more effective than WT PSTPIP1 in inducing pyrin activation. Therefore, constitutive ligation and activation of pyrin by mutant PSTPIP1 proteins explain the autoinflammatory phenotype seen in PAPA syndrome.
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