2n1f

Structural highlights

Function

[ASC_MOUSE] 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. 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]}

References

1. ↑ Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature. 2004 Jul 8;430(6996):213-8. Epub 2004 Jun 9. PMID:15190255 doi:10.1038/nature02664
2. ↑ Yamamoto M, Yaginuma K, Tsutsui H, Sagara J, Guan X, Seki E, Yasuda K, Yamamoto M, Akira S, Nakanishi K, Noda T, Taniguchi S. ASC is essential for LPS-induced activation of procaspase-1 independently of TLR-associated signal adaptor molecules. Genes Cells. 2004 Nov;9(11):1055-67. PMID:15507117 doi:http://dx.doi.org/10.1111/j.1365-2443.2004.00789.x
3. ↑ Ippagunta SK, Malireddi RK, Shaw PJ, Neale GA, Vande Walle L, Green DR, Fukui Y, Lamkanfi M, Kanneganti TD. The inflammasome adaptor ASC regulates the function of adaptive immune cells by controlling Dock2-mediated Rac activation and actin polymerization. Nat Immunol. 2011 Sep 4;12(10):1010-6. doi: 10.1038/ni.2095. PMID:21892172 doi:http://dx.doi.org/10.1038/ni.2095
4. ↑ Pierini R, Juruj C, Perret M, Jones CL, Mangeot P, Weiss DS, Henry T. AIM2/ASC triggers caspase-8-dependent apoptosis in Francisella-infected caspase-1-deficient macrophages. Cell Death Differ. 2012 Oct;19(10):1709-21. doi: 10.1038/cdd.2012.51. Epub 2012, May 4. PMID:22555457 doi:10.1038/cdd.2012.51
5. ↑ Sborgi L, Ravotti F, Dandey VP, Dick MS, Mazur A, Reckel S, Chami M, Scherer S, Huber M, Bockmann A, Egelman EH, Stahlberg H, Broz P, Meier BH, Hiller S. Structure and assembly of the mouse ASC inflammasome by combined NMR spectroscopy and cryo-electron microscopy. Proc Natl Acad Sci U S A. 2015 Oct 27;112(43):13237-42. doi:, 10.1073/pnas.1507579112. Epub 2015 Oct 13. PMID:26464513 doi:http://dx.doi.org/10.1073/pnas.1507579112