Role of Post-Translational Modifications of cGAS in Innate Immunity
Abstract
:1. Introduction
2. Post-Translational Modifications of cGAS
2.1. Phosphorylation
2.2. Acetylation
2.3. Glutamylation
2.4. Ubiquitination
2.5. SUMOylation
2.6. Caspase-Mediated Cleavage
3. Conclusions and Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AIM2 | absent in melanoma 2 |
AKT1 | AKT serine/threonine kinase 1 |
BLK kinase | B lymphocyte kinase |
C-terminal | carboxyl-terminal |
CCPs | cytosolic carboxypeptidases |
CDK1 | cyclin-dependent kinase 1 |
cGAMP | cyclic GMP-AMP |
cGAS | cyclic GMP-AMP synthase |
dsRNA | double-stranded RNA |
ER | endoplasmic reticulum |
ERGIC | endoplasmic-reticulum–Golgi intermediate compartment |
G3BP1 | GTPase-activating protein SH3 domain-binding protein 1 |
HDAC3 | histone deacetylase 3 |
HSV-1 | herpes simplex virus 1 |
IFN | interferon |
IL-1 | interleukin-1 |
IRFs | interferon regulatory factors |
KAT5 | lysine acetyltransferase 5 |
LPS | lipopolysaccharides |
mtDNA | mitochondrial DNA |
N-terminal | amino-terminal |
NONO | non-POU domain-containing octamer binding protein |
NSAID | non-steroidal anti-inflammatory drug |
NTase | nucleotidyltransferase |
PAMPs | pathogen-associated molecular patterns |
PKB | protein kinase B |
PP1 | protein phosphatase 1 |
PQBP1 | Polyglutamine binding protein 1 |
PRRs | pattern recognition receptors |
PTMs | post-translational modifications |
RIG-I | retinoic acid-inducible gene I |
RLRs | retinoic acid-inducible gene I (RIG-I)-like receptors |
SASP | senescence-associated secretory phenotype |
SENP2 | SUMO1 specific peptidase 2 |
SLE | systemic lupus erythematosus |
ssRNA | single-stranded RNA |
STING | stimulator of interferon genes |
SUMO | small ubiquitin-related modifier |
TBK1 | TANK-binding kinase 1 |
TLR4 | toll-like receptor 4 |
TTL | tubulin tyrosine ligase |
TTLL | tubulin tyrosine ligase-like |
References
- Sun, L.; Wu, J.; Du, F.; Chen, X.; Chen, Z.J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 2013, 339, 786–791. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, X.; Wu, J.X.; Du, F.H.; Xu, H.; Sun, L.J.; Chen, Z.; Brautigam, C.A.; Zhang, X.W.; Chen, Z.J.J. The Cytosolic DNA Sensor cGAS Forms an Oligomeric Complex with DNA and Undergoes Switch-like Conformational Changes in the Activation Loop. Cell Rep. 2014, 6, 421–430. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, X.; Shu, C.; Yi, G.H.; Chaton, C.T.; Shelton, C.L.; Diao, J.S.; Zuo, X.B.; Kao, C.C.; Herr, A.B.; Li, P.W. Cyclic GMP-AMP Synthase Is Activated by Double-Stranded DNA-Induced Oligomerization. Immunity 2013, 39, 1019–1031. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, J.; Sun, L.; Chen, X.; Du, F.; Shi, H.; Chen, C.; Chen, Z.J. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 2013, 339, 826–830. [Google Scholar] [CrossRef] [Green Version]
- Kranzusch, P.J.; Lee, A.S.; Berger, J.M.; Doudna, J.A. Structure of human cGAS reveals a conserved family of second-messenger enzymes in innate immunity. Cell Rep. 2013, 3, 1362–1368. [Google Scholar] [CrossRef] [Green Version]
- Gao, P.; Ascano, M.; Wu, Y.; Barchet, W.; Gaffney, B.L.; Zillinger, T.; Serganov, A.A.; Liu, Y.; Jones, R.A.; Hartmann, G.; et al. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell 2013, 153, 1094–1107. [Google Scholar] [CrossRef] [Green Version]
- Civril, F.; Deimling, T.; de Oliveira Mann, C.C.; Ablasser, A.; Moldt, M.; Witte, G.; Hornung, V.; Hopfner, K.P. Structural mechanism of cytosolic DNA sensing by cGAS. Nature 2013, 498, 332–337. [Google Scholar] [CrossRef] [Green Version]
- Diner, E.J.; Burdette, D.L.; Wilson, S.C.; Monroe, K.M.; Kellenberger, C.A.; Hyodo, M.; Hayakawa, Y.; Hammond, M.C.; Vance, R.E. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep. 2013, 3, 1355–1361. [Google Scholar] [CrossRef] [Green Version]
- Ablasser, A.; Goldeck, M.; Cavlar, T.; Deimling, T.; Witte, G.; Rohl, I.; Hopfner, K.P.; Ludwig, J.; Hornung, V. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 2013, 498, 380–384. [Google Scholar] [CrossRef] [Green Version]
- Volkman, H.E.; Cambier, S.; Gray, E.E.; Stetson, D.B. Tight nuclear tethering of cGAS is essential for preventing autoreactivity. Elife 2019. [Google Scholar] [CrossRef]
- Barnett, K.C.; Coronas-Serna, J.M.; Zhou, W.; Ernandes, M.J.; Cao, A.; Kranzusch, P.J.; Kagan, J.C. Phosphoinositide Interactions Position cGAS at the Plasma Membrane to Ensure Efficient Distinction between Self- and Viral DNA. Cell 2019, 176, 1432–1446.e11. [Google Scholar] [CrossRef] [Green Version]
- Yang, H.; Wang, H.; Ren, J.; Chen, Q.; Chen, Z.J. cGAS is essential for cellular senescence. Proc. Natl. Acad. Sci. USA 2017, 114, E4612–E4620. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gentili, M.; Lahaye, X.; Nadalin, F.; Nader, G.P.F.; Lombardi, E.P.; Herve, S.; De Silva, N.S.; Rookhuizen, D.C.; Zueva, E.; Goudot, C.; et al. The N-Terminal Domain of cGAS Determines Preferential Association with Centromeric DNA and Innate Immune Activation in the Nucleus. Cell Rep. 2019, 26, 3798. [Google Scholar] [CrossRef]
- Liu, H.; Zhang, H.; Wu, X.; Ma, D.; Wu, J.; Wang, L.; Jiang, Y.; Fei, Y.; Zhu, C.; Tan, R.; et al. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature 2018, 563, 131–136. [Google Scholar] [CrossRef] [PubMed]
- Mackenzie, K.J.; Carroll, P.; Martin, C.A.; Murina, O.; Fluteau, A.; Simpson, D.J.; Olova, N.; Sutcliffe, H.; Rainger, J.K.; Leitch, A.; et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 2017, 548, 461–465. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pathare, G.R.; Decout, A.; Gluck, S.; Cavadini, S.; Makasheva, K.; Hovius, R.; Kempf, G.; Weiss, J.; Kozicka, Z.; Guey, B.; et al. Structural mechanism of cGAS inhibition by the nucleosome. Nature 2020. [Google Scholar] [CrossRef] [PubMed]
- Michalski, S.; de Oliveira Mann, C.C.; Stafford, C.; Witte, G.; Bartho, J.; Lammens, K.; Hornung, V.; Hopfner, K.P. Structural basis for sequestration and autoinhibition of cGAS by chromatin. Nature 2020. [Google Scholar] [CrossRef]
- Kujirai, T.; Zierhut, C.; Takizawa, Y.; Kim, R.; Negishi, L.; Uruma, N.; Hirai, S.; Funabiki, H.; Kurumizaka, H. Structural basis for the inhibition of cGAS by nucleosomes. Science 2020. [Google Scholar] [CrossRef]
- Zhao, B.; Xu, P.; Rowlett, C.M.; Jing, T.; Shinde, O.; Lei, Y.; West, A.P.; Liu, W.R.; Li, P. The Molecular Basis of Tight Nuclear Tethering and Inactivation of cGAS. Nature 2020. [Google Scholar] [CrossRef]
- Boyer, J.A.; Spangler, C.J.; Strauss, J.D.; Cesmat, A.P.; Liu, P.; McGinty, R.K.; Zhang, Q. Structural basis of nucleosome-dependent cGAS inhibition. Science 2020. [Google Scholar] [CrossRef]
- Zierhut, C.; Funabiki, H. Regulation and Consequences of cGAS Activation by Self-DNA. Trends Cell Biol. 2020, 30, 594–605. [Google Scholar] [CrossRef] [PubMed]
- Dou, Z.; Ghosh, K.; Vizioli, M.G.; Zhu, J.; Sen, P.; Wangensteen, K.J.; Simithy, J.; Lan, Y.; Lin, Y.; Zhou, Z.; et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 2017, 550, 402–406. [Google Scholar] [CrossRef] [Green Version]
- Gluck, S.; Guey, B.; Gulen, M.F.; Wolter, K.; Kang, T.W.; Schmacke, N.A.; Bridgeman, A.; Rehwinkel, J.; Zender, L.; Ablasser, A. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 2017, 19, 1061–1070. [Google Scholar] [CrossRef] [PubMed]
- Takahashi, A.; Loo, T.M.; Okada, R.; Kamachi, F.; Watanabe, Y.; Wakita, M.; Watanabe, S.; Kawamoto, S.; Miyata, K.; Barber, G.N.; et al. Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells. Nat. Commun. 2018, 9, 1249. [Google Scholar] [CrossRef] [PubMed]
- Zierhut, C.; Yamaguchi, N.; Paredes, M.; Luo, J.D.; Carroll, T.; Funabiki, H. The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death. Cell 2019, 178, 302–315.e23. [Google Scholar] [CrossRef] [PubMed]
- Nassour, J.; Radford, R.; Correia, A.; Fuste, J.M.; Schoell, B.; Jauch, A.; Shaw, R.J.; Karlseder, J. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature 2019, 565, 659–663. [Google Scholar] [CrossRef]
- Hopfner, K.P.; Hornung, V. Molecular mechanisms and cellular functions of cGAS-STING signalling. Nat. Rev. Mol. Cell Biol. 2020. [Google Scholar] [CrossRef]
- Jiang, H.; Xue, X.; Panda, S.; Kawale, A.; Hooy, R.M.; Liang, F.; Sohn, J.; Sung, P.; Gekara, N.O. Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death. EMBO J. 2019, 38, e102718. [Google Scholar] [CrossRef]
- Kwon, J.; Bakhoum, S.F. The Cytosolic DNA-Sensing cGAS-STING Pathway in Cancer. Cancer Discov. 2020, 10, 26–39. [Google Scholar] [CrossRef]
- Yoh, S.M.; Schneider, M.; Seifried, J.; Soonthornvacharin, S.; Akleh, R.E.; Olivieri, K.C.; De Jesus, P.D.; Ruan, C.; de Castro, E.; Ruiz, P.A.; et al. PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1. Cell 2015, 161, 1293–1305. [Google Scholar] [CrossRef] [Green Version]
- Liu, Z.S.; Cai, H.; Xue, W.; Wang, M.; Xia, T.; Li, W.J.; Xing, J.Q.; Zhao, M.; Huang, Y.J.; Chen, S.; et al. G3BP1 promotes DNA binding and activation of cGAS. Nat. Immunol. 2019, 20, 18–28. [Google Scholar] [CrossRef] [PubMed]
- Lian, H.; Wei, J.; Zang, R.; Ye, W.; Yang, Q.; Zhang, X.N.; Chen, Y.D.; Fu, Y.Z.; Hu, M.M.; Lei, C.Q.; et al. ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response. Nat. Commun. 2018, 9, 3349. [Google Scholar] [CrossRef] [PubMed]
- Schoggins, J.W.; MacDuff, D.A.; Imanaka, N.; Gainey, M.D.; Shrestha, B.; Eitson, J.L.; Mar, K.B.; Richardson, R.B.; Ratushny, A.V.; Litvak, V.; et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 2014, 505, 691–695. [Google Scholar] [CrossRef] [PubMed]
- Seo, G.J.; Yang, A.; Tan, B.; Kim, S.; Liang, Q.; Choi, Y.; Yuan, W.; Feng, P.; Park, H.S.; Jung, J.U. Akt Kinase-Mediated Checkpoint of cGAS DNA Sensing Pathway. Cell Rep. 2015, 13, 440–449. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhong, L.; Hu, M.M.; Bian, L.J.; Liu, Y.; Chen, Q.; Shu, H.B. Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis. Cell Discov. 2020, 6, 26. [Google Scholar] [CrossRef] [PubMed]
- Li, M.; Shu, H.B. Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response. Protein Cell 2020, 11, 584–599. [Google Scholar] [CrossRef] [PubMed]
- Song, Z.M.; Lin, H.; Yi, X.M.; Guo, W.; Hu, M.M.; Shu, H.B. KAT5 acetylates cGAS to promote innate immune response to DNA virus. Proc. Natl. Acad. Sci. USA 2020. [Google Scholar] [CrossRef]
- Dai, J.; Huang, Y.J.; He, X.; Zhao, M.; Wang, X.; Liu, Z.S.; Xue, W.; Cai, H.; Zhan, X.Y.; Huang, S.Y.; et al. Acetylation Blocks cGAS Activity and Inhibits Self-DNA-Induced Autoimmunity. Cell 2019, 176, 1447–1460.e14. [Google Scholar] [CrossRef] [Green Version]
- Xia, P.; Ye, B.; Wang, S.; Zhu, X.; Du, Y.; Xiong, Z.; Tian, Y.; Fan, Z. Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity. Nat. Immunol. 2016, 17, 369–378. [Google Scholar] [CrossRef]
- Wang, Q.; Huang, L.; Hong, Z.; Lv, Z.; Mao, Z.; Tang, Y.; Kong, X.; Li, S.; Cui, Y.; Liu, H.; et al. The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated innate immune response. PLoS Pathog. 2017, 13, e1006264. [Google Scholar] [CrossRef]
- Seo, G.J.; Kim, C.; Shin, W.J.; Sklan, E.H.; Eoh, H.; Jung, J.U. TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing. Nat. Commun. 2018, 9, 613. [Google Scholar] [CrossRef] [Green Version]
- Liu, Z.S.; Zhang, Z.Y.; Cai, H.; Zhao, M.; Mao, J.; Dai, J.; Xia, T.; Zhang, X.M.; Li, T. RINCK-mediated monoubiquitination of cGAS promotes antiviral innate immune responses. Cell Biosci. 2018, 8, 35. [Google Scholar] [CrossRef] [Green Version]
- Chen, M.; Meng, Q.; Qin, Y.; Liang, P.; Tan, P.; He, L.; Zhou, Y.; Chen, Y.; Huang, J.; Wang, R.F.; et al. TRIM14 Inhibits cGAS Degradation Mediated by Selective Autophagy Receptor p62 to Promote Innate Immune Responses. Mol. Cell 2016, 64, 105–119. [Google Scholar] [CrossRef] [Green Version]
- Guo, Y.; Jiang, F.; Kong, L.; Li, B.; Yang, Y.; Zhang, L.; Liu, B.; Zheng, Y.; Gao, C. Cutting Edge: USP27X Deubiquitinates and Stabilizes the DNA Sensor cGAS to Regulate Cytosolic DNA-Mediated Signaling. J. Immunol. 2019, 203, 2049–2054. [Google Scholar] [CrossRef]
- Hu, M.M.; Yang, Q.; Xie, X.Q.; Liao, C.Y.; Lin, H.; Liu, T.T.; Yin, L.; Shu, H.B. Sumoylation Promotes the Stability of the DNA Sensor cGAS and the Adaptor STING to Regulate the Kinetics of Response to DNA Virus. Immunity 2016, 45, 555–569. [Google Scholar] [CrossRef] [Green Version]
- Cui, Y.; Yu, H.S.; Zheng, X.; Peng, R.; Wang, Q.; Zhou, Y.; Wang, R.; Wang, J.H.; Qu, B.; Shen, N.; et al. SENP7 Potentiates cGAS Activation by Relieving SUMO-Mediated Inhibition of Cytosolic DNA Sensing. Plos Pathog. 2017, 13, e1006156. [Google Scholar] [CrossRef]
- White, M.J.; McArthur, K.; Metcalf, D.; Lane, R.M.; Cambier, J.C.; Herold, M.J.; van Delft, M.F.; Bedoui, S.; Lessene, G.; Ritchie, M.E.; et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 2014, 159, 1549–1562. [Google Scholar] [CrossRef] [Green Version]
- Wang, Y.; Ning, X.; Gao, P.; Wu, S.; Sha, M.; Lv, M.; Zhou, X.; Gao, J.; Fang, R.; Meng, G.; et al. Inflammasome Activation Triggers Caspase-1-Mediated Cleavage of cGAS to Regulate Responses to DNA Virus Infection. Immunity 2017, 46, 393–404. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ning, X.; Wang, Y.; Jing, M.; Sha, M.; Lv, M.; Gao, P.; Zhang, R.; Huang, X.; Feng, J.M.; Jiang, Z. Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3. Mol. Cell 2019, 74, 19–31.e7. [Google Scholar] [CrossRef] [PubMed]
- Diehl, N.; Schaal, H. Make Yourself at Home: Viral Hijacking of the PI3K/Akt Signaling Pathway. Viruses 2013, 5, 3192–3212. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Verdin, E.; Ott, M. 50 years of protein acetylation: From gene regulation to epigenetics, metabolism and beyond. Nat. Rev. Mol. Cell Biol. 2015, 16, 258–264. [Google Scholar] [CrossRef] [PubMed]
- Garnham, C.P.; Vemu, A.; Wilson-Kubalek, E.M.; Yu, I.; Szyk, A.; Lander, G.C.; Milligan, R.A.; Roll-Mecak, A. Multivalent Microtubule Recognition by Tubulin Tyrosine Ligase-like Family Glutamylases. Cell 2015, 161, 1112–1123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rogowski, K.; van Dijk, J.; Magiera, M.M.; Bosc, C.; Deloulme, J.C.; Bosson, A.; Peris, L.; Gold, N.D.; Lacroix, B.; Bosch Grau, M.; et al. A family of protein-deglutamylating enzymes associated with neurodegeneration. Cell 2010, 143, 564–578. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Janke, C.; Rogowski, K.; van Dijk, J. Polyglutamylation: A fine-regulator of protein function? ’Protein Modifications: Beyond the usual suspects’ review series. Embo Rep. 2008, 9, 636–641. [Google Scholar] [CrossRef] [Green Version]
- Patil, G.; Li, S. Tripartite motif proteins: An emerging antiviral protein family. Future Virol. 2019, 14, 107–122. [Google Scholar] [CrossRef] [PubMed]
- Flotho, A.; Melchior, F. Sumoylation: A regulatory protein modification in health and disease. Annu. Rev. Biochem. 2013, 82, 357–385. [Google Scholar] [CrossRef] [PubMed]
- Wilkinson, K.A.; Henley, J.M. Mechanisms, regulation and consequences of protein SUMOylation. Biochem. J. 2010, 428, 133–145. [Google Scholar] [CrossRef] [Green Version]
- Lahaye, X.; Gentili, M.; Silvin, A.; Conrad, C.; Picard, L.; Jouve, M.; Zueva, E.; Maurin, M.; Nadalin, F.; Knott, G.J.; et al. NONO Detects the Nuclear HIV Capsid to Promote cGAS-Mediated Innate Immune Activation. Cell 2018, 175, 488–501.e22. [Google Scholar] [CrossRef] [Green Version]
- Du, M.; Chen, Z.J. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science 2018, 361, 704–709. [Google Scholar] [CrossRef] [Green Version]
- Li, X.D.; Wu, J.; Gao, D.; Wang, H.; Sun, L.; Chen, Z.J. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 2013, 341, 1390–1394. [Google Scholar] [CrossRef] [Green Version]
- Fischer, H.; Tschachler, E.; Eckhart, L. Cytosolic DNA sensing through cGAS and STING is inactivated by gene mutations in pangolins. Apoptosis 2020, 25, 474–480. [Google Scholar] [CrossRef] [PubMed]
- Song, B.; Greco, T.M.; Lum, K.K.; Taber, C.; Cristea, I.M. The DNA Sensor cGAS is Decorated by Acetylation and Phosphorylation Modifications in the Context of Immune Signaling. Mol. Cell. Proteom. 2020. [Google Scholar] [CrossRef] [PubMed]
PTM Site (h: Human cGAS; m: Mouse cGAS) | PTM | Enzyme | Function | Reference |
---|---|---|---|---|
S291 (m) | Phosphorylation | AKT | Suppresses cGAS enzymatic activity | [34] |
S291 (m) | Phosphorylation | CDK1 | Suppresses cGAS enzymatic activity during mitosis | [35] |
Y215 (h) | Phosphorylation | BLK | Facilitates the cytosolic retention of cGAS | [14] |
S291 (m) | Dephosphorylation | PP1 | Restores cGAS activity in the cytoplasm upon mitotic exit | [35] |
S420 (m) | Dephosphorylation | PPP6C | Prevents cGAS from binding to GTP and inhibit cGAS activity | [36] |
K47 (h), K56 (h), K62 (h), and K83(h) | Acetylation | KAT5 | Promotes cGAS DNA binding activity and activation | [37] |
K384 (h), K394 (h), and K414 (h) | Deacetylation | HDAC3 | Required for cGAS activation | [38] |
E272 (m) | Polyglutamylation | TTLL6 | Dampens the DNA binding activity of cGAS | [39] |
E302 (m) | Monoglutamylation | TTLL4 | Blocks cGAS enzymatic activity | [39] |
E302 (m) | Deglutamylation | CCP5 | Removes the monolutamylation of cGAS | [39] |
E272 (m) | Deglutamylation | CCP6 | Removes the polyglutamylation of cGAS | [39] |
K173 (m) and K184 (m) | Polyubiquitination | RNF185 | Medaites K27-linked polyubiquitination and promotes enzymatic activity of cGAS | [40] |
K335 (m) | Monoubiquitination | TRIM56 | Promotes cGAS dimerization and DNA-binding activity | [41] |
Unknown | Monoubiquitination | TRIM41 | Promotes cGAS activation | [42] |
K414 (h) | Deubiquitination | USP14 | Cleaves the K48-linked polyubiquitination of cGAS and prevents cGAS degradation | [43] |
Unknown | Deubiquitination | USP27X | Cleaves the K48-linked polyubiquitination of cGAS and prevents cGAS degradation | [44] |
K217 (m) and K464 (m) | SUMOylation | TRIM38 | Prevents cGAS from K48-linked polyubiquitination and degradation | [45] |
K217 (m) and K464 (m) | DeSUMOylation | SENP2 | Promotes cGAS degradation | [45] |
K335 (m), K372 (m), and K382 (m) | DeSUMOylation | SENP7 | Promotes cGAS dimerization and DNA-binding activity | [46] |
Unknown | Cleavage | Caspase 9 | Suppresses mtDNA-induced type I IFN production | [47] |
Unknown | Cleavage | Caspase 3/7 | Suppresses mtDNA-induced type I IFN production | [47] |
D140 (h) and D157 (h) | Cleavage | Caspase 1 | Inhibits cGAS activity | [48] |
D319 (h) | Cleavage | Caspase 3 | Inhibits cGAS activity | [49] |
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Wu, Y.; Li, S. Role of Post-Translational Modifications of cGAS in Innate Immunity. Int. J. Mol. Sci. 2020, 21, 7842. https://doi.org/10.3390/ijms21217842
Wu Y, Li S. Role of Post-Translational Modifications of cGAS in Innate Immunity. International Journal of Molecular Sciences. 2020; 21(21):7842. https://doi.org/10.3390/ijms21217842
Chicago/Turabian StyleWu, Yakun, and Shitao Li. 2020. "Role of Post-Translational Modifications of cGAS in Innate Immunity" International Journal of Molecular Sciences 21, no. 21: 7842. https://doi.org/10.3390/ijms21217842