Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants.
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.
Yu
Je-Wook
JW
Department of Biochemistry and Molecular Biology, Center for Apoptosis Research, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Fernandes-Alnemri
Teresa
T
Datta
Pinaki
P
Wu
Jianghong
J
Juliana
Christine
C
Solorzano
Leobaldo
L
McCormick
Margaret
M
Zhang
ZhiJia
Z
Alnemri
Emad S
ES
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000378:metabolism*; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D010505:Familial Mediterranean Fever / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005822:Genetic Vectors; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate; D053583:Interleukin-1beta / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D015739:Nocodazole / Q000494:pharmacology; D010641:Phenotype; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D000071198:Pyrin; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D014162:Transfection; D050257:Tubulin Modulators / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D053583:Interleukin-1beta; C000604192:MEFV protein, human; D046912:Multiprotein Complexes; C486382:PSTPIP1 protein, human; C402202:PYCARD protein, human; D000071198:Pyrin; D011993:Recombinant Fusion Proteins; D050257:Tubulin Modulators; D020170:Caspase 1; D015739:Nocodazole; D003078:Colchicine