title: The PYRIN-CARD protein ASC is an activating adaptor for caspase-1.
abstract: The PYRIN and CARD domains are members of the six-helix bundle death domain-fold superfamily that mediates assembly of large signaling complexes in the apoptotic and inflammatory signaling pathways. Here we show that the PYRIN-CARD protein ASC functions as a caspase-1-activating adaptor. ASC interacted specifically with procaspase-1 via CARD-CARD interactions and induced its oligomerization. Consistent with these results ectopic expression of full-length ASC, but not its isolated CARD or PYRIN domain, with procaspase-1 induced activation of procaspase-1 and processing of pro-interleukin-1beta in transfected cells. Substitution of the PYRIN domain of ASC with an inducible FKBP12 oligomerization domain produced a molecule that can induce caspase-1 activation in response to stimulation with the oligomerization drug AP20187, suggesting that the PYRIN domain functions as an oligomerization domain, whereas the CARD domain functions as the effector domain in the caspase-1 activation pathway. Furthermore stable expression of an isolated CARD of ASC in THP-1 cells diminished interleukin-1beta generation in response to pro-inflammatory cytokines. These results indicate that ASC is involved in the caspase-1 signaling pathway by mediating the assembly of a caspase-1-inflammasome signaling complex in response to pro-inflammatory cytokine stimulation.
authors.affiliation: Center for Apoptosis Research and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Srinivasa M
authors.initials: SM
authors.lastname: Srinivasula
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Poyet
authors.forename: Marjaneh
authors.initials: M
authors.lastname: Razmara
authors.forename: Pinaki
authors.initials: P
authors.lastname: Datta
authors.forename: ZhiJia
authors.initials: Z
authors.lastname: Zhang
authors.forename: Emad S
authors.initials: ES
authors.lastname: Alnemri
mesh_terms: D001798:Blood Proteins / Q000737:chemistry; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000737:chemistry; D020170:Caspase 1 / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000502:physiology*; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005799:Genes, Dominant; D005822:Genetic Vectors; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007375:Interleukin-1 / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry; D000071198:Pyrin; D014162:Transfection
chemical_list: D001798:Blood Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D007375:Interleukin-1; C000604192:MEFV protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D011506:Proteins; D000071198:Pyrin; D005982:Glutathione Transferase; D020170:Caspase 1