| Structural highlights
Function
[ASC_HUMAN] Functions as key mediator in apoptosis and inflammation. Promotes caspase-mediated apoptosis involving predominantly caspase-8 and also caspase-9 in a probable cell type-specific manner. Involved in activation of the mitochondrial apoptotic pathway, promotes caspase-8-dependent proteolytic maturation of BID independently of FADD in certain cell types and also mediates mitochondrial translocation of BAX and activates BAX-dependent apoptosis coupled to activation of caspase-9, -2 and -3. Involved in macrophage pyroptosis, a caspase-1-dependent inflammatory form of cell death and is the major constituent of the ASC pyroptosome which forms upon potassium depletion and rapidly recruits and activates caspase-1. In innate immune response believed to act as an integral adapter in the assembly of the inflammasome which activates caspase-1 leading to processing and secretion of proinflammatory cytokines. The function as activating adapter in different types of inflammasomes is mediated by the DAPIN and CARD domains and their homotypic interactions. Required for recruitment of caspase-1 to inflammasomes containing certain pattern recognition receptors, such as NLRP2, NLRP3, AIM2 and probably IFI16. In the NLRP1 and NLRC4 inflammasomes seems not be required but facilitates the processing of procaspase-1. In cooperation with NOD2 involved in an inflammasome activated by bacterial muramyl dipeptide leading to caspase-1 activation. May be involved in DDX58-triggered proinflammatory responses and inflammasome activation. Isoform 2 may have a regulating effect on the function as inflammasome adapter. Isoform 3 seems to inhibit inflammasome-mediated maturation of interleukin-1 beta. In collaboration with AIM2 which detects cytosolic double-stranded DNA may also be involved in a caspase-1-independent cell death that involves caspase-8. In adaptive immunity may be involved in maturation of dendritic cells to stimulate T-cell immunity and in cytoskeletal rearrangements coupled to chemotaxis and antigen uptake may be involved in post-transcriptional regulation of the guanine nucleotide exchange factor DOCK2; the latter function is proposed to involve the nuclear form. Also involved in transcriptional activation of cytokines and chemokines independent of the inflammasome; this function may involve AP-1, NF-kappa-B, MAPK and caspase-8 signaling pathways. For regulation of NF-kappa-B activating and inhibiting functions have been reported. Modulates NF-kappa-B induction at the level of the IKK complex by inhibiting kinase activity of CHUK and IKBK. Proposed to compete with RIPK2 for association with CASP1 thereby down-regulating CASP1-mediated RIPK2-dependent NF-kappa-B activation and activating interleukin-1 beta processing.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The human protein ASC is a key mediator in apoptosis and inflammation. Through its two death domains (pyrin and CARD) ASC interacts with cell death executioners, acts as an essential adapter for inflammasome integrity, and oligomerizes into functional supramolecular assemblies. However, these functions are not understood at the structural-dynamic level. This study reports the solution structure and interdomain dynamics of full-length ASC. The pyrin and CARD domains are structurally independent six-helix bundle motifs connected by a 23-residue linker. The CARD structure reveals two distinctive characteristics; helix 1 is not fragmented as in all other known CARDs, and its electrostatic surface shows a uniform distribution of positive and negative charges, whereas these are commonly separated into two areas in other death domains. The linker adopts residual structure resulting in a back-to-back orientation of the domains, which avoids steric interference of each domain with the binding site of the other. NMR relaxation experiments show that the linker is flexible despite the residual structure. This flexibility could help expand the relative volume occupied by each domain, thus increasing the capture radius for effectors. Based on the ASC structure, a tentative model is proposed to illustrate how ASC oligomerizes via CARD and pyrin homophilic interactions. Moreover, ASC oligomers have been analyzed by atomic force microscopy, showing a predominant species of disk-like particles of approximately 12-nm diameter and approximately 1-nm height. Taken together, these results provide structural insight into the behavior of ASC as an adapter molecule.
Structure and interdomain dynamics of apoptosis-associated speck-like protein containing a CARD (ASC).,de Alba E J Biol Chem. 2009 Nov 20;284(47):32932-41. Epub 2009 Sep 15. PMID:19759015[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Matsushita K, Takeoka M, Sagara J, Itano N, Kurose Y, Nakamura A, Taniguchi S. A splice variant of ASC regulates IL-1beta release and aggregates differently from intact ASC. Mediators Inflamm. 2009;2009:287387. doi: 10.1155/2009/287387. Epub 2009 Sep 15. PMID:19759850 doi:http://dx.doi.org/10.1155/2009/287387
- ↑ McConnell BB, Vertino PM. Activation of a caspase-9-mediated apoptotic pathway by subcellular redistribution of the novel caspase recruitment domain protein TMS1. Cancer Res. 2000 Nov 15;60(22):6243-7. PMID:11103777
- ↑ Stehlik C, Fiorentino L, Dorfleutner A, Bruey JM, Ariza EM, Sagara J, Reed JC. The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor kappaB activation pathways. J Exp Med. 2002 Dec 16;196(12):1605-15. PMID:12486103
- ↑ Masumoto J, Dowds TA, Schaner P, Chen FF, Ogura Y, Li M, Zhu L, Katsuyama T, Sagara J, Taniguchi S, Gumucio DL, Nunez G, Inohara N. ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis. Biochem Biophys Res Commun. 2003 Mar 28;303(1):69-73. PMID:12646168
- ↑ Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004 Mar;20(3):319-25. PMID:15030775
- ↑ Ohtsuka T, Ryu H, Minamishima YA, Macip S, Sagara J, Nakayama KI, Aaronson SA, Lee SW. ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. Nat Cell Biol. 2004 Feb;6(2):121-8. Epub 2004 Jan 18. PMID:14730312 doi:http://dx.doi.org/10.1038/ncb1087
- ↑ Sarkar A, Duncan M, Hart J, Hertlein E, Guttridge DC, Wewers MD. ASC directs NF-kappaB activation by regulating receptor interacting protein-2 (RIP2) caspase-1 interactions. J Immunol. 2006 Apr 15;176(8):4979-86. PMID:16585594
- ↑ Taxman DJ, Zhang J, Champagne C, Bergstralh DT, Iocca HA, Lich JD, Ting JP. Cutting edge: ASC mediates the induction of multiple cytokines by Porphyromonas gingivalis via caspase-1-dependent and -independent pathways. J Immunol. 2006 Oct 1;177(7):4252-6. PMID:16982856
- ↑ Fernandes-Alnemri T, Wu J, Yu JW, Datta P, Miller B, Jankowski W, Rosenberg S, Zhang J, Alnemri ES. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 2007 Sep;14(9):1590-604. Epub 2007 Jun 29. PMID:17599095 doi:http://dx.doi.org/10.1038/sj.cdd.4402194
- ↑ Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell. 2007 Mar 9;25(5):713-24. PMID:17349957 doi:10.1016/j.molcel.2007.01.032
- ↑ Hasegawa M, Kawase K, Inohara N, Imamura R, Yeh WC, Kinoshita T, Suda T. Mechanism of ASC-mediated apoptosis: bid-dependent apoptosis in type II cells. Oncogene. 2007 Mar 15;26(12):1748-56. Epub 2006 Sep 11. PMID:16964285 doi:http://dx.doi.org/10.1038/sj.onc.1209965
- ↑ Bryan NB, Dorfleutner A, Rojanasakul Y, Stehlik C. Activation of inflammasomes requires intracellular redistribution of the apoptotic speck-like protein containing a caspase recruitment domain. J Immunol. 2009 Mar 1;182(5):3173-82. doi: 10.4049/jimmunol.0802367. PMID:19234215 doi:http://dx.doi.org/10.4049/jimmunol.0802367
- ↑ Hasegawa M, Imamura R, Motani K, Nishiuchi T, Matsumoto N, Kinoshita T, Suda T. Mechanism and repertoire of ASC-mediated gene expression. J Immunol. 2009 Jun 15;182(12):7655-62. doi: 10.4049/jimmunol.0800448. PMID:19494289 doi:http://dx.doi.org/10.4049/jimmunol.0800448
- ↑ Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009 Mar 26;458(7237):509-13. doi: 10.1038/nature07710. Epub 2009 Jan 21. PMID:19158676 doi:10.1038/nature07710
- ↑ Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E, Fitzgerald KA. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009 Mar 26;458(7237):514-8. doi: 10.1038/nature07725. Epub 2009 Jan 21. PMID:19158675 doi:10.1038/nature07725
- ↑ Bryan NB, Dorfleutner A, Kramer SJ, Yun C, Rojanasakul Y, Stehlik C. Differential splicing of the apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) regulates inflammasomes. J Inflamm (Lond). 2010 May 18;7:23. doi: 10.1186/1476-9255-7-23. PMID:20482797 doi:http://dx.doi.org/10.1186/1476-9255-7-23
- ↑ Taxman DJ, Holley-Guthrie EA, Huang MT, Moore CB, Bergstralh DT, Allen IC, Lei Y, Gris D, Ting JP. The NLR adaptor ASC/PYCARD regulates DUSP10, mitogen-activated protein kinase (MAPK), and chemokine induction independent of the inflammasome. J Biol Chem. 2011 Jun 3;286(22):19605-16. doi: 10.1074/jbc.M111.221077. Epub 2011, Apr 12. PMID:21487011 doi:http://dx.doi.org/10.1074/jbc.M111.221077
- ↑ Guo X, Dhodapkar KM. Central and overlapping role of Cathepsin B and inflammasome adaptor ASC in antigen presenting function of human dendritic cells. Hum Immunol. 2012 Sep;73(9):871-8. doi: 10.1016/j.humimm.2012.06.008. Epub 2012, Jun 22. PMID:22732093 doi:http://dx.doi.org/10.1016/j.humimm.2012.06.008
- ↑ Liepinsh E, Barbals R, Dahl E, Sharipo A, Staub E, Otting G. The death-domain fold of the ASC PYRIN domain, presenting a basis for PYRIN/PYRIN recognition. J Mol Biol. 2003 Oct 3;332(5):1155-63. PMID:14499617
- ↑ de Alba E. Structure and interdomain dynamics of apoptosis-associated speck-like protein containing a CARD (ASC). J Biol Chem. 2009 Nov 20;284(47):32932-41. Epub 2009 Sep 15. PMID:19759015 doi:10.1074/jbc.M109.024273
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