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Pyrin Activates the ASC Pyroptosome in Response to Engagement by Autoinflammatory PSTPIP1 Mutants

Authors
 Je-Wook Yu  ;  Teresa Fernandes-Alnemri  ;  Emad S. Alnemri  ;  ZhiJia Zhang  ;  Margaret McCormick  ;  Leobaldo Solorzano  ;  Christine Juliana  ;  Jianghong Wu  ;  Pinaki Datta 
Citation
 MOLECULAR CELL, Vol.28(2) : 214-227, 2007 
Journal Title
MOLECULAR CELL
ISSN
 1097-2765 
Issue Date
2007
Abstract
The molecular mechanism by which mutations in the cytoskeleton-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.
Full Text
http://www.sciencedirect.com/science/article/pii/S1097276507006429
DOI
10.1016/j.molcel.2007.08.029
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Yu, Je Wook(유제욱) ORCID logo https://orcid.org/0000-0001-5943-4071
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/97153
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