The PYRIN-CARD Protein ASC Is an Activating Adaptor for Caspase-1*

By S. Srinivasula, J. Poyet, M. Razmara, P. Datta, Zhijia Zhang, E. Alnemri. Journal of Biological Chemistry, 2002

609 citations recorded by the source corpus.

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-1β 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-1β 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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9aa4b33888ee7fa9c2854ec2949e7c2ff512b401

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. J. Tschopp
2. G. Núñez
3. Fabio Martinon
4. L. Franchi
5. E. Latz
6. Shizuo Akira
7. Edward A. Miao
8. T. Kanneganti

In Molecular Biology

1. J. Tschopp
2. G. Núñez
3. T. Kanneganti
4. Fabio Martinon
5. C. A. Dinarello
6. E. Latz
7. L. Franchi
8. M. Lamkanfi

Citations in the corpus

• Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1β via Ipaf (2006, background): “However, the CARD of Ipaf also interacts with the CARD of AS”
• The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation (2007, background): “It links the PYD-containing NLR family member to procaspase-1, using its PYD to interact with the PYD of the NLRs and its CARD to interact with the CARD of procaspase-1.(5,8) Gene-targeted deletion of ASC in mice revealed that ASC is essential for activation of caspase-1 and generation of mature IL-”
• Differential requirement for Caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing (2010, background): “Asc serves as a linker between the PYRIN domain of the NLR/PYHIN sensors and the CARD domain of pro-Caspase-1 (Srinivasula et al., 2002).”
• Nonclassical IL-1β Secretion Stimulated by P2X7 Receptors Is Dependent on Inflammasome Activation and Correlated with Exosome Release in Murine Macrophages1 (2007, background): “The adapter or scaffolding proteins for inflammasome activation include apoptosis-associated speck-like protein containing a Cterminal CARD (ASC)/Pycard (6), which contains a PYRIN domain in addition to its CARD site, and members of the nu-”
• NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. (2018, background): “ASC is composed of 2 death domains; an N-terminal PYD and a C-terminal CARD, both of them known to promote oligomeric homotypic interactions.(75)”
• NALPs: a novel protein family involved in inflammation (2003, background): “50 ), although these interactions have recently been questione”
• De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. (2002, background): “In addition to the potential proinflammatory effect of alterations in NF-κB signaling in white blood cells, cryopyrin has recently been shown to regulate IL-1β production through a pathway involving first PYRIN domain interactions between cryopyrin and ASC, and then homotypic caspase recruitment dom”
• NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. (2004, background): “containing protein called ASC binds and activates procaspase-1 (Martinon et al., 2002; Srinivasula et al., 2002; Wang et al., 2002).”