Nuclear cGAS: sequestration and beyond

Abstract

The cyclic GMP-AMP (cGAMP) synthase (cGAS) has been identified as a cytosolic double stranded DNA sensor that plays a pivotal role in the type I interferon and inflammation responses via the STING-dependent signaling pathway. In the past several years, a growing body of evidence has revealed that cGAS is also localized in the nucleus where it is associated with distinct nuclear substructures such as nucleosomes, DNA replication forks, the double-stranded breaks, and centromeres, suggesting that cGAS may have other functions in addition to its role in DNA sensing. However, while the innate immune function of cGAS is well established, the non-canonical nuclear function of cGAS remains poorly understood. Here, we review our current understanding of the complex nature of nuclear cGAS and point to open questions on the novel roles and the mechanisms of action of this protein as a key regulator of cell nuclear function, beyond its well-established role in dsDNA sensing and innate immune response.

Keywords

cGAS / STING / innate immunity / nuclear translocation / DNA damage repair / micronuclei

References

[1] Abe T, Barber GN(2014) Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NFkappaB activation through TBK1. J Virol 88:5328–5341

[2] Ablasser A, Chen ZJ(2019) cGAS in action: Expanding roles in immunity and inflammation. Science 363:eaat8657

[3] Andreeva L, Hiller B, Kostrewa D, Lassig C, de Oliveira Mann CC, Jan Drexler D, Maiser A, Gaidt M,Leonhardt H, Hornung V(2017) cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders. Nature 549:394–398

[4] Antonin W, Neumann H(2016) Chromosome condensation and decondensation during mitosis. Curr Opin Cell Biol 40:15–22

[5] Artandi SE, DePinho RA(2000) A critical role for telomeres in suppressing and facilitating carcinogenesis. Curr Opin Genet Dev 10:39–46

[6] Bai J, Cervantes C, He S, He J, Plasko GR, Wen J, Li Z, Yin D, Zhang C, Liu M(2020) Mitochondrial stress-activated cGAS STING pathway inhibits thermogenic program and contributes to overnutrition-induced obesity in mice. Commun Biol 3:257

[7] Bai J, Cervantes C, Liu J, He S, Zhou H, Zhang B, Cai H, Yin D, Hu D, Li Z(2017) DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA releaseactivated cGAS-cGAMP-STING pathway. Proc Natl Acad Sci U S A 114:12196–12201

[8] Bai J, Liu F(2019) The cGAS-cGAMP-STING pathway: a molecular link between immunity and metabolism. Diabetes 68:1099–1108

[9] Bakhoum SF, Ngo B, Laughney AM, Cavallo JA, Murphy CJ, Ly P, Shah P, Sriram RK, Watkins TBK, Taunk NK(2018) Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 553:467–472

[10] Balka KR, Louis C, Saunders TL, Smith AM, Calleja DJ, D’Silva DB, Moghaddas F, Tailler M, Lawlor KE, Zhan Y(2020) TBK1 and IKKepsilon act redundantly to mediate STING-induced NFkappaB responses in myeloid cells. Cell Rep 31:107492

[11] Barnett KC, Coronas-Serna JM, Zhou W, Ernandes MJ, Cao A, Kranzusch PJ, Kagan JC(2019) Phosphoinositide interactions position cGAS at the plasma membrane to ensure efficient distinction between self- and viral DNA. Cell 176:1432–1446

[12] Boyer JA, Spangler CJ, Strauss JD, Cesmat AP, Liu P, McGinty RK, Zhang Q(2020) Structural basis of nucleosome-dependent cGAS inhibition. Science 370:450–454

[13] Cao D, Han X, Fan X, Xu RM, Zhang X(2020) Structural basis for nucleosome-mediated inhibition of cGAS activity. Cell Res 30:1088–1097

[14] Chen H, Chen H, Zhang J, Wang Y, Simoneau A, Yang H, Levine AS, Zou L, Chen Z, Lan L(2020) cGAS suppresses genomic instability as a decelerator of replication forks. Sci Adv 6:108293

[15] Chen Q, Sun L, Chen ZJ(2016) Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol 17:1142–1149

[16] Civril F, Deimling T, de Oliveira Mann CC, Ablasser A, Moldt M, Witte G, Hornung V, Hopfner KP(2013) Structural mechanism of cytosolic DNA sensing by cGAS. Nature 498:332–337

[17] Cui S, Yu Q, Chu L, Cui Y, Ding M, Wang Q, Wang H, Chen Y, Liu X, Wang C(2020) Nuclear cGAS Functions Non-canonically to Enhance Antiviral Immunity via Recruiting Methyltransferase Prmt5. Cell Rep 33:108490

[18] Du M, Chen ZJ(2018) DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science 361:704–709

[19] Fang R, Wang C, Jiang Q, Lv M, Gao P, Yu X, Mu P, Zhang R, Bi S, Feng JM(2017) NEMO-IKKbeta are essential for IRF3 and NF-kappaB activation in the cGAS-STING pathway. J Immunol 199:3222–3233

[20] Fenech M, Kirsch-Volders M, Natarajan AT, Surralles J, Crott JW, Parry J, Norppa H, Eastmond DA, Tucker JD, Thomas P(2011) Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells. Mutagenesis 26:125–132

[21] Gekara NO, Jiang H(2019) The innate immune DNA sensor cGAS: a membrane, cytosolic, or nuclear protein? Sci Signal 12:12–89

[22] Gentili M, Lahaye X, Nadalin F, Nader GPF, Puig Lombardi E, Herve S, De Silva NS, Rookhuizen DC, Zueva E, Goudot C(2019) The N-terminal domain of cGAS determines preferential association with centromeric DNA and innate immune activation in the nucleus. Cell Rep 26:2377–2393

[23] Gluck S, Guey B, Gulen MF, Wolter K, Kang TW, Schmacke NA, Bridgeman A, Rehwinkel J, Zender L, Ablasser A(2017) Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol 19:1061–1070

[24] Guey B, Wischnewski M, Decout A, Makasheva K, Kaynak M, Sakar MS, Fierz B, Ablasser A(2020) BAF restricts cGAS on nuclear DNA to prevent innate immune activation. Science 369:823–828

[25] Hakem R(2008) DNA-damage repair; the good, the bad, and the ugly. EMBO J 27:589–605

[26] Harding SM, Benci JL, Irianto J, Discher DE, Minn AJ, Greenberg RA(2017) Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548:466–470

[27] Hauer MH, Gasser SM(2017) Chromatin and nucleosome dynamics in DNA damage and repair. Genes Dev 31:2204–2221

[28] Hong C, Tijhuis AE, Foijer F(2019) The cGAS paradox: contrasting roles for cGAS-STING pathway in chromosomal instability. Cells 8:1228

[29] Hooy RM, Sohn J(2018) The allosteric activation of cGAS underpins its dynamic signaling landscape. Elife 7:35–136

[30] Janssen A, van der Burg M, Szuhai K, Kops GJ, Medema RH(2011) Chromosome segregation errors as a cause of DNA damage and structural chromosome aberrations. Science 333:1895–1898

[31] Jiang H, Xue X, Panda S, Kawale A, Hooy RM, Liang F, Sohn J, Sung P, Gekara NO(2019) Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death. EMBO J 38:102718

[32] Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, White E(2007) Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 21:1621–1635

[33] Kranzusch PJ(2019) cGAS and CD-NTase enzymes: structure, mechanism, and evolution. Curr Opin Struct Biol 59:178–187

[34] Kujirai T, Zierhut C, Takizawa Y, Kim R, Negishi L, Uruma N, Hirai S, Funabiki H, Kurumizaka H(2020) Structural basis for the inhibition of cGAS by nucleosomes. Science 370:455–458

[35] Lahaye X, Gentili M, Silvin A, Conrad C, Picard L, Jouve M, Zueva E, Maurin M, Nadalin F, Knott GJ(2018) NONO detects the nuclear HIV capsid to promote cGAS-mediated innate immune activation. Cell 175:488–501

[36] Lengauer C, Kinzler KW, Vogelstein B(1998) Genetic instabilities in human cancers. Nature 396:643–649

[37] Li T, Huang T, Du M, Chen X, Du F, Ren J, Chen ZJ(2021) Phosphorylation and chromatin tethering prevent cGAS activation during mitosis. Science 371(6535):5386

[38] Li X, Shu C, Yi G, Chaton CT, Shelton CL, Diao J, Zuo X, Kao CC, Herr AB, Li P(2013) Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization. Immunity 39:1019–1031

[39] Liu H, Zhang H, Wu X, Ma D, Wu J, Wang L, Jiang Y, Fei Y, Zhu C, Tan R(2018) Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature 563:131–136

[40] Luecke S, Holleufer A, Christensen MH, Jonsson KL, Boni GA, Sorensen LK, Johannsen M, Jakobsen MR, Hartmann R, Paludan SR(2017) cGAS is activated by DNA in a lengthdependent manner. EMBO Rep 18:1707–1715

[41] Luger K, Dechassa ML, Tremethick DJ(2012) New insights into nucleosome and chromatin structure: an ordered state or a disordered affair? Nat Rev Mol Cell Biol 13:436–447

[42] Mackenzie KJ, Carroll P, Martin CA, Murina O, Fluteau A, Simpson DJ, Olova N, Sutcliffe H, Rainger JK, Leitch A(2017) cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548:461–465

[43] Martire S, Banaszynski LA(2020) The roles of histone variants in fine-tuning chromatin organization and function. Nat Rev Mol Cell Biol 21:522–541

[44] Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, Chen G, Jin S, White E(2007) Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 21:1367–1381

[45] Michalski S, de Oliveira Mann CC, Stafford CA, Witte G, Bartho J, Lammens K, Hornung V, Hopfner KP(2020) Structural basis for sequestration and autoinhibition of cGAS by chromatin. Nature 587:678–682

[46] Motwani M, Pesiridis S, Fitzgerald KA(2019) DNA sensing by the cGAS-STING pathway in health and disease. Nat Rev Genet 20:657–674

[47] Nassour J, Radford R, Correia A, Fuste JM, Schoell B, Jauch A, Shaw RJ, Karlseder J(2019) Autophagic cell death restricts chromosomal instability during replicative crisis. Nature 565:659–663

[48] Orzalli MH, Broekema NM, Diner BA, Hancks DC, Elde NC, Cristea IM, Knipe DM(2015) cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection. Proc Natl Acad Sci U S A 112:E1773–1781

[49] Pathare GR, Decout A, Gluck S, Cavadini S, Makasheva K, Hovius R, Kempf G, Weiss J, Kozicka Z, Guey B(2020) Structural mechanism of cGAS inhibition by the nucleosome. Nature. https://doi.org/10.1038/s41586-020-2750-6

[50] Raab M, Gentili M, de Belly H, Thiam HR, Vargas P, Jimenez AJ, Lautenschlaeger F, Voituriez R, Lennon-Dumenil AM, Manel N(2016) ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death. Science 352:359–362

[51] Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM(1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273:5858–5868

[52] Sun H, Huang Y, Mei S, Xu F, Liu X, Zhao F, Yin L, Zhang D, Wei L, Wu C(2021) A nuclear export signal is required for cGAS to sense cytosolic DNA. Cell Rep 34:108586

[53] Sun L, Wu J, Du F, Chen X, Chen ZJ(2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339:786–791

[54] Uggenti C, Lepelley A, Depp M, Badrock AP, Rodero MP, El-Daher MT, Rice GI, Dhir S, Wheeler AP, Dhir A(2020) cGASmediated induction of type I interferon due to inborn errors of histone pre-mRNA processing. Nat Genet 52:1364–1372

[55] Uhlorn BL, Gamez ER, Li S, Campos SK(2020) Attenuation of cGAS/STING activity during mitosis. Life Sci Alliance 3(9): e201900636

[56] Volkman HE, Cambier S, Gray EE, Stetson DB(2019) Tight nuclear tethering of cGAS is essential for preventing autoreactivity. Elife 8:e47491

[57] Wang H, Zang C, Ren M, Shang M, Wang Z, Peng X, Zhang Q, Wen X, Xi Z, Zhou C(2020) Cellular uptake of extracellular nucleosomes induces innate immune responses by binding and activating cGMP-AMP synthase (cGAS). Sci Rep 10:15385

[58] West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM, Lang SM, Bestwick M, Duguay BA, Raimundo N, MacDuff DA(2015) Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520:553–557

[59] Wilkins BJ, Rall NA, Ostwal Y, Kruitwagen T, Hiragami-Hamada K, Winkler M, Barral Y, Fischle W, Neumann H(2014) A cascade of histone modifications induces chromatin condensation in mitosis. Science 343:77–80

[60] Wu J, Sun L, Chen X, Du F, Shi H, Chen C, Chen ZJ(2013) Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339:826–830

[61] Wu X, Wu FH, Wang X, Wang L, Siedow JN, Zhang W, Pei ZM(2014) Molecular evolutionary and structural analysis of the cytosolic DNA sensor cGAS and STING. Nucleic Acids Res 42:8243–8257

[62] Xia P, Ye B, Wang S, Zhu X, Du Y, Xiong Z, Tian Y, Fan Z(2016) Erratum: Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity. Nat Immunol 17:469

[63] Xie W, Lama L, Adura C, Tomita D, Glickman JF, Tuschl T, Patel DJ(2019) Human cGAS catalytic domain has an additional DNAbinding interface that enhances enzymatic activity and liquidphase condensation. Proc Natl Acad Sci U S A 116:11946–11955

[64] Yang H, Wang H, Ren J, Chen Q, Chen ZJ(2017) cGAS is essential for cellular senescence. Proc Natl Acad Sci U S A 114:E4612–E4620

[65] Zhang X, Wu J, Du F, Xu H, Sun L, Chen Z, Brautigam CA, Zhang X, Chen ZJ(2014) The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop. Cell Rep 6:421–430

[66] Zhao B, Xu P, Rowlett CM, Jing T, Shinde O, Lei Y, West AP, Liu WR, Li P(2020) The molecular basis of tight nuclear tethering and inactivation of cGAS. Nature 587:673–677

[67] Zhao M, Wang F, Wu J, Cheng Y, Cao Y, Wu X, Ma M, Tang F, Liu Z, Liu H(2021) CGAS is a micronucleophagy receptor for the clearance of micronuclei. Autophagy 24:1–17

[68] Zhong L, Hu MM, Bian LJ, Liu Y, Chen Q, Shu HB(2020) Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis. Cell Discov 6:26

[69] Zhou W, Whiteley AT, de Oliveira Mann CC, Morehouse BR, Nowak RP, Fischer ES, Gray NS, Mekalanos JJ, Kranzusch PJ(2018) Structure of the human cGAS-DNA complex reveals enhanced control of immune surveillance. Cell 174:300–311

[70] Zierhut C, Yamaguchi N, Paredes M, Luo JD, Carroll T, Funabiki H(2019) The cytoplasmic DNA sensor cGAS promotes mitotic cell death. Cell 178:302–315

RIGHTS & PERMISSIONS

2021 The Author(s)