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AIM2 Inflammasome Assembly and Signaling

  • Bing Wang
  • Yuan TianEmail author
  • Qian YinEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1172)

Abstract

AIM2 (absent in melanoma 2) is a cytoplasmic sensor of double-stranded DNA from pathogens or damaged cellular organelles. It recruits ASC (apoptosis-associated specklike protein containing a CARD) and caspase-1 to form the AIM2 inflammasome, activate caspase-1, and elicit inflammatory responses via cytokine maturation and pyroptotic cell death. Structural studies from X-ray crystallography, NMR, and cryo-EM have revealed many details in AIM2 inflammasome activation, assembly, and regulation. Many principles learned from AIM2 inflammasome also apply to other inflammasomes. In this chapter, we discuss the interactions between dsDNA and AIM2-like receptors, between AIM2 and adaptor protein ASC, and between ASC and caspase-1 with the focus on helical filament assembly formed by PYD and CARD domains.

Keywords

AIM2 ASC Caspase-1 Inflammasome HIN PYD CARD Helical filament p202 POP COP 

Notes

Acknowledgements

This work was supported by the US National Institutes of Health grant R00AI108793 and start-up funds from Florida State University.

References

  1. 1.
    Broz P, Dixit VM (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol 16(7):407–420CrossRefGoogle Scholar
  2. 2.
    Park HH, Lo YC, Lin SC, Wang L, Yang JK, Wu H (2007) The death domain superfamily in intracellular signaling of apoptosis and inflammation. Annu Rev Immunol 25:561–586CrossRefGoogle Scholar
  3. 3.
    Yin Q, Sester DP, Tian Y, Hsiao YS, Lu A, Cridland JA, Sagulenko V, Thygesen SJ, Choubey D, Hornung V, Walz T, Stacey KJ, Wu H (2013) Molecular mechanism for p202-mediated specific inhibition of AIM2 inflammasome activation. Cell Rep 4(2):327–339CrossRefGoogle Scholar
  4. 4.
    Lu A, Magupalli VG, Ruan J, Yin Q, Atianand MK, Vos MR, Schroder GF, Fitzgerald KA, Wu H, Egelman EH (2014) Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156(6):1193–1206CrossRefGoogle Scholar
  5. 5.
    Theobald DL, Mitton-Fry RM, Wuttke DS (2003) Nucleic acid recognition by OB-fold proteins. Annu Rev Biophys Biomol Struct 32:115–133CrossRefGoogle Scholar
  6. 6.
    Jin T, Perry A, Jiang J, Smith P, Curry JA, Unterholzner L, Jiang Z, Horvath G, Rathinam VA, Johnstone RW, Hornung V, Latz E, Bowie AG, Fitzgerald KA, Xiao TS (2012) Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. Immunity 36(4):561–571CrossRefGoogle Scholar
  7. 7.
    Li H, Wang J, Wang J, Cao LS, Wang ZX, Wu JW (2014) Structural mechanism of DNA recognition by the p202 HINa domain: insights into the inhibition of Aim2-mediated inflammatory signalling. Acta Crystallogr F Struct Biol Commun 70(Pt 1):21–29CrossRefGoogle Scholar
  8. 8.
    Liao JC, Lam R, Brazda V, Duan S, Ravichandran M, Ma J, Xiao T, Tempel W, Zuo X, Wang YX, Chirgadze NY, Arrowsmith CH (2011) Interferon-inducible protein 16: insight into the interaction with tumor suppressor p53. Structure 19(3):418–429CrossRefGoogle Scholar
  9. 9.
    Ru H, Ni X, Zhao L, Crowley C, Ding W, Hung LW, Shaw N, Cheng G, Liu ZJ (2013) Structural basis for termination of AIM2-mediated signaling by p202. Cell ResGoogle Scholar
  10. 10.
    Burckstummer T, Baumann C, Bluml S, Dixit E, Durnberger G, Jahn H, Planyavsky M, Bilban M, Colinge J, Bennett KL, Superti-Furga G (2009) An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol 10(3):266–272CrossRefGoogle Scholar
  11. 11.
    Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM, Hodgson S, Hardy LL, Garceau V, Sweet MJ, Ross IL, Hume DA, Stacey KJ (2009) HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 323(5917):1057–1060CrossRefGoogle Scholar
  12. 12.
    Bochkarev A, Pfuetzner RA, Edwards AM, Frappier L (1997) Structure of the single-stranded-DNA-binding domain of replication protein A bound to DNA. Nature 385(6612):176–181CrossRefGoogle Scholar
  13. 13.
    Yang H, Jeffrey PD, Miller J, Kinnucan E, Sun Y, Thoma NH, Zheng N, Chen PL, Lee WH, Pavletich NP (2002) BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297(5588):1837–1848CrossRefGoogle Scholar
  14. 14.
    Ferrao R, Wu H (2012) Helical assembly in the death domain (DD) superfamily. Curr Opin Struct Biol 22(2):241–247CrossRefGoogle Scholar
  15. 15.
    Jin T, Perry A, Smith P, Jiang J, Xiao TS (2013) Structure of the absent in melanoma 2 (AIM2) pyrin domain provides insights into the mechanisms of AIM2 autoinhibition and inflammasome assembly. J Biol Chem 288(19):13225–13235CrossRefGoogle Scholar
  16. 16.
    Lu A, Kabaleeswaran V, Fu T, Magupalli VG, Wu H (2014) Crystal structure of the F27G AIM2 PYD mutant and similarities of its self-association to DED/DED interactions. J Mol Biol 426(7):1420–1427CrossRefGoogle Scholar
  17. 17.
    Hou X, Niu X (2015) The NMR solution structure of AIM2 PYD domain from Mus musculus reveals a distinct alpha2-alpha3 helix conformation from its human homologues. Biochem Biophys Res Commun 461(2):396–400CrossRefGoogle Scholar
  18. 18.
    Natarajan A, Ghose R, Hill JM (2006) Structure and dynamics of ASC2, a pyrin domain-only protein that regulates inflammatory signaling. J Biol Chem 281(42):31863–31875CrossRefGoogle Scholar
  19. 19.
    Wang H, Yang L, Niu X (2016) Conformation switching of AIM2 PYD domain revealed by NMR relaxation and MD simulation. Biochem Biophys Res Commun 473(2):636–641CrossRefGoogle Scholar
  20. 20.
    Morrone SR, Matyszewski M, Yu X, Delannoy M, Egelman EH, Sohn J (2015) Assembly-driven activation of the AIM2 foreign-dsDNA sensor provides a polymerization template for downstream ASC. Nat Commun 6:7827CrossRefGoogle Scholar
  21. 21.
    Lu A, Li Y, Yin Q, Ruan J, Yu X, Egelman E, Wu H (2015) Plasticity in PYD assembly revealed by cryo-EM structure of the PYD filament of AIM2. Cell Discov 1Google Scholar
  22. 22.
    Matyszewski M, Morrone SR, Sohn J (2018) Digital signaling network drives the assembly of the AIM2-ASC inflammasome. Proc Natl Acad Sci USA 115(9):E1963–E1972CrossRefGoogle Scholar
  23. 23.
    Man SM, Kanneganti TD (2015) Regulation of inflammasome activation. Immunol Rev 265(1):6–21CrossRefGoogle Scholar
  24. 24.
    de Alba E (2009) Structure and interdomain dynamics of apoptosis-associated speck-like protein containing a CARD (ASC). J Biol Chem 284(47):32932–32941CrossRefGoogle Scholar
  25. 25.
    Liepinsh E, Barbals R, Dahl E, Sharipo A, Staub E, Otting G (2003) The death-domain fold of the ASC PYRIN domain, presenting a basis for PYRIN/PYRIN recognition. J Mol Biol 332(5):1155–1163CrossRefGoogle Scholar
  26. 26.
    Li Y, Huang Y, Cao X, Yin X, Jin X, Liu S, Jiang J, Jiang W, Xiao TS, Zhou R, Cai G, Hu B, Jin T (2018) Functional and structural characterization of zebrafish ASC. FEBS J 285(14):2691–2707CrossRefGoogle Scholar
  27. 27.
    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 (2015) Structure and assembly of the mouse ASC inflammasome by combined NMR spectroscopy and cryo-electron microscopy. Proc Natl Acad Sci USA 112(43):13237–13242CrossRefGoogle Scholar
  28. 28.
    Li Y, Fu TM, Lu A, Witt K, Ruan J, Shen C, Wu H (2018) Cryo-EM structures of ASC and NLRC4 CARD filaments reveal a unified mechanism of nucleation and activation of caspase-1. Proc Natl Acad Sci USA 115(43):10845–10852CrossRefGoogle Scholar
  29. 29.
    Dick MS, Sborgi L, Ruhl S, Hiller S, Broz P (2016) ASC filament formation serves as a signal amplification mechanism for inflammasomes. Nat Commun 7:11929CrossRefGoogle Scholar
  30. 30.
    Lu A, Li Y, Schmidt FI, Yin Q, Chen S, Fu TM, Tong AB, Ploegh HL, Mao Y, Wu H (2016) Molecular basis of caspase-1 polymerization and its inhibition by a new capping mechanism. Nat Struct Mol Biol 23(5):416–425CrossRefGoogle Scholar
  31. 31.
    Matyszewski M, Zheng W, Lueck J, Antiochos B, Egelman EH, Sohn J (2018) Cryo-EM structure of the NLRC4(CARD) filament provides insights into how symmetric and asymmetric supramolecular structures drive inflammasome assembly. J Biol Chem 293(52):20240–20248CrossRefGoogle Scholar
  32. 32.
    Wang PH, Ye ZW, Deng JJ, Siu KL, Gao WW, Chaudhary V, Cheng Y, Fung SY, Yuen KS, Ho TH, Chan CP, Zhang Y, Kok KH, Yang W, Chan CP, Jin DY (2018) Inhibition of AIM2 inflammasome activation by a novel transcript isoform of IFI16. EMBO Rep 19(10)Google Scholar
  33. 33.
    Dorfleutner A, Chu L, Stehlik C (2015) Inhibiting the inflammasome: one domain at a time. Immunol Rev 265(1):205–216CrossRefGoogle Scholar
  34. 34.
    Humke EW, Shriver SK, Starovasnik MA, Fairbrother WJ, Dixit VM (2000) ICEBERG: a novel inhibitor of interleukin-1beta generation. Cell 103(1):99–111CrossRefGoogle Scholar
  35. 35.
    Indramohan M, Stehlik C, Dorfleutner A (2018) COPs and POPs patrol inflammasome activation. J Mol Biol 430(2):153–173CrossRefGoogle Scholar
  36. 36.
    Schmidt FI, Lu A, Chen JW, Ruan J, Tang C, Wu H, Ploegh HL (2016) A single domain antibody fragment that recognizes the adaptor ASC defines the role of ASC domains in inflammasome assembly. J Exp Med 213(5):771–790CrossRefGoogle Scholar
  37. 37.
    Wu B, Peisley A, Tetrault D, Li Z, Egelman EH, Magor KE, Walz T, Penczek PA, Hur S (2014) Molecular imprinting as a signal-activation mechanism of the viral RNA sensor RIG-I. Mol Cell 55(4):511–523CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Biological ScienceFlorida State UniversityTallahasseeUSA
  2. 2.Institute of Molecular BiophysicsFlorida State UniversityTallahasseeUSA

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