Regulatory role of phosphorylation in NLRP3 inflammasome activation

Huang Yi; Zhou Rongbin

doi:10.52396/JUST-2021-0079

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Regulatory role of phosphorylation in NLRP3 inflammasome activation

Huang Yi^1,2,
Zhou Rongbin^{1

,}

1.
Hefei National Laboratory for Physical Sciences at the Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China
2.
Wuxi School of Medicine, Jiangnan University, Wuxi 214122, China

Cite this:

https://doi.org/10.52396/JUST-2021-0079

Received Date: 17 March 2021
Rev Recd Date: 18 April 2021
Publish Date: 31 May 2021

Abstract Full text PDF

Abstract

Abstract

NLRP3 is a pattern recognition receptor localized in the cytoplasm that belongs to the NOD-like receptor family. Upon activation by a wide range of danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), NLRP3 recruits the adaptor protein ASC and the cysteine protease pro-caspase-1 to form a multiprotein complex called the NLRP3 inflammasome. The primary function of the NLRP3 inflammasome is to maintain homeostasis by facilitating the immune response to remove pathogens and danger signals. However, aberrant activation of the NLRP3 inflammasome also causes a variety of inflammatory diseases.Therefore, NLRP3 inflammasome activation must be precisely regulated. Recently, various kinases and phosphatases have been reported to control the NLRP3 inflammasome activation, suggesting that phosphorylation plays a vital role in regulating the inflammasome activation. In this review, we summarize how various kinases and phosphatases control the NLRP3 inflammasome activation and provide an overview of the regulatory role of phosphorylation in the NLRP3 inflammasome activation. Further, we discuss the potential pharmacologically compounds that target NLRP3-related kinases or phosphatases for the treatment of inflammasome-driven diseases.

Abstract

NLRP3 is a pattern recognition receptor localized in the cytoplasm that belongs to the NOD-like receptor family. Upon activation by a wide range of danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), NLRP3 recruits the adaptor protein ASC and the cysteine protease pro-caspase-1 to form a multiprotein complex called the NLRP3 inflammasome. The primary function of the NLRP3 inflammasome is to maintain homeostasis by facilitating the immune response to remove pathogens and danger signals. However, aberrant activation of the NLRP3 inflammasome also causes a variety of inflammatory diseases.Therefore, NLRP3 inflammasome activation must be precisely regulated. Recently, various kinases and phosphatases have been reported to control the NLRP3 inflammasome activation, suggesting that phosphorylation plays a vital role in regulating the inflammasome activation. In this review, we summarize how various kinases and phosphatases control the NLRP3 inflammasome activation and provide an overview of the regulatory role of phosphorylation in the NLRP3 inflammasome activation. Further, we discuss the potential pharmacologically compounds that target NLRP3-related kinases or phosphatases for the treatment of inflammasome-driven diseases.

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References(45)

References

[1]	Swanson K V, Deng M, Ting J P. The NLRP3 inflammasome: Molecular activation and regulation to therapeutics. Nat Rev Immunol, 2019, 19(8): 477-489.
[2]	Hara H, Tsuchiya K, Kawamura I, et al. Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat Immunol, 2013, 14(12): 1247-1255.
[3]	Martinon F, Burns K, Tschopp J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell, 2002, 10(2): 417-426.
[4]	He W T, Wan H, Hu L, et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res, 2015, 25(12): 1285-1298.
[5]	Shi J, Zhao Y, Wang K, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature, 2015, 526(7575): 660-665.
[6]	Kelley N, Jeltema D, Duan Y, et al. The NLRP3 inflammasome: An overview of mechanisms of activation and regulation. Int J Mol Sci, 2019, 20(13): 3328.
[7]	Gong T, Jiang W, Zhou R. Control of inflammasome activation by phosphorylation. Trends Biochem Sci, 2018, 43(9): 685-699.
[8]	Song N, Li T. Regulation of NLRP3 inflammasome by phosphorylation. Front Immunol, 2018, 9: 2305.
[9]	Ubersax J A, Ferrell J E, Jr. Mechanisms of specificity in protein phosphorylation. Nat Rev Mol Cell Biol, 2007, 8(7): 530-541.
[10]	Ardito F, Giuliani M, Perrone D, et al. The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review). Int J Mol Med, 2017, 40(2): 271-280.
[11]	He Y, Zeng M Y, Yang D, et al. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature, 2016, 530(7590): 354-357.
[12]	Schmid-Burgk J L, Chauhan D, Schmidt T, et al. A Genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) screen identifies NEK7 as an essential component of NLRP3 inflammasome activation. J Biol Chem, 2016, 291(1): 103-109.
[13]	Shi H, Wang Y, Li X, et al. NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat Immunol, 2016, 17(3): 250-258.
[14]	Spalinger M R, Kasper S, Gottier C, et al. NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22. J Clin Invest, 2016, 126(5): 1783-1800.
[15]	Spalinger M R, Lang S, Gottier C, et al. PTPN22 regulates NLRP3-mediated IL1B secretion in an autophagy-dependent manner. Autophagy, 2017, 13(9): 1590-1601.
[16]	Xiao Y, Tang J, Lin G, et al. Tyrosine phosphorylation of NLRP3 by Src family protein tyrosine kinase Lyn suppresses NLRP3 inflammasome activation. J Immunol,2020,204:68.19.
[17]	Shio M T, Eisenbarth S C, Savaria M, et al. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathog, 2009, 5(8): e1000559.
[18]	Becker C E, Creagh E M, O’Neill L A. Rab39a binds caspase-1 and is required for caspase-1-dependent interleukin-1beta secretion. J Biol Chem, 2009, 284(50): 34531-34537.
[19]	Mortimer L, Moreau F, MacDonald J A, et al. NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations. Nat Immunol, 2016, 17(10): 1176-1186.
[20]	Guo C, Xie S, Chi Z, et al. Bile Acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity, 2016, 45(4): 802-816.
[21]	Zhang Z, Meszaros G, He W T, et al. Protein kinase D at the Golgi controls NLRP3 inflammasome activation. J Exp Med, 2017, 214(9): 2671-2693.
[22]	Dufies O, Doye A, Courjon J, et al. Escherichia coli Rho GTPase-activating toxin CNF1 mediates NLRP3 inflammasome activation via p21-activated kinases-1/2 during bacteraemia in mice. Nat Microbiol, 2021, 6(3): 401-412.
[23]	Ting J P, Lovering R C, Alnemri E S, et al. The NLR gene family: A standard nomenclature. Immunity, 2008, 28(3): 285-287.
[24]	Stutz A, Kolbe C C, Stahl R, et al. NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain. J Exp Med, 2017, 214(6): 1725-1736.
[25]	Huang Y, Wang H, Hao Y, et al. Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity. Nat Cell Biol, 2020, 22(6): 716-727.
[26]	Zhang A, Xing J, Xia T, et al. EphA2 phosphorylates NLRP3 and inhibits inflammasomes in airway epithelial cells. EMBO Rep, 2020, 21(7): e49666.
[27]	Song N, Liu Z S, Xue W, et al. NLRP3 phosphorylation is an essential priming event for inflammasome activation. Mol Cell, 2017, 68(1): 185-197.e6.
[28]	Ren G, Zhang X, Xiao Y, et al. ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination. EMBO J, 2019, 38(6):e100376.
[29]	Martin B N, Wang C, Willette-Brown J, et al. IKKalpha negatively regulates ASC-dependent inflammasome activation. Nat Commun, 2014, 5: 4977.
[30]	Mambwe B, Neo K, Javanmard Khameneh H, et al. Tyrosine dephosphorylation of ASC modulates the activation of the NLRP3 and AIM2 inflammasomes. Front Immunol, 2019, 10: 1556.
[31]	Chung I C, OuYang C N, Yuan S N, et al. Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis. Sci Rep, 2016, 6: 36214.
[32]	Gavrilin M A, Prather E R, Vompe A D, et al. cAbl kinase regulates inflammasome activation and pyroptosis via ASC phosphorylation. J Immunol, 2021, 206(6):1329-1336.
[33]	Okada M, Matsuzawa A, Yoshimura A, et al. The lysosome rupture-activated TAK1-JNK pathway regulates NLRP3 inflammasome activation. J Biol Chem, 2014, 289(47): 32926-32936.
[34]	Basak C, Pathak S K, Bhattacharyya A, et al. NF-kappaB- and C/EBPbeta-driven interleukin-1beta gene expression and PAK1-mediated caspase-1 activation play essential roles in interleukin-1beta release from Helicobacter pylori lipopolysaccharide-stimulated macrophages. J Biol Chem, 2005, 280(6): 4279-4288.
[35]	Yang X D, Li W, Zhang S, et al. PLK4 deubiquitination by Spata2-CYLD suppresses NEK7-mediated NLRP3 inflammasome activation at the centrosome. EMBO J, 2020, 39(2): e102201.
[36]	Samir P, Kesavardhana S, Patmore D M, et al. DDX3X acts as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome. Nature, 2019, 573(7775): 590-594.
[37]	Gu L, Fullam A, Brennan R, et al. Human DEAD box helicase 3 couples IkappaB kinase epsilon to interferon regulatory factor 3 activation. Mol Cell Biol, 2013, 33(10): 2004-2015.
[38]	Ito M, Shichita T, Okada M, et al. Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat Commun, 2015, 6: 7360.
[39]	Liu X, Pichulik T, Wolz O O, et al. Human NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase. J Allergy Clin Immunol, 2017, 140(4): 1054-1067.e10.
[40]	Weber A N R. Targeting the NLRP3 inflammasome via BTK. Front Cell Dev Biol, 2021, 9: 630479.
[41]	Purvis G S D, Collino M, Aranda-Tavio H, et al. Inhibition of Bruton’s TK regulates macrophage NF-kappaB and NLRP3 inflammasome activation in metabolic inflammation. Br J Pharmacol, 2020, 177(19): 4416-4432.
[42]	O’Riordan C E, Purvis G S D, Collotta D, et al. Bruton’styrosine kinase inhibition attenuates the cardiac dysfunction caused by cecal ligation and puncture in mice. Front Immunol, 2019, 10: 2129.
[43]	Hussein M, Chai D C, Kyama C M, et al. c-Jun NH2-terminal kinase inhibitor bentamapimod reduces induced endometriosis in baboons: An assessor-blind placebo-controlled randomized study. Fertil Steril, 2016, 105(3): 815-824.e5.
[44]	Zhang P, Liu Y, Jia L, et al. SP600125, a JNK-specific inhibitor, regulates in vitro auricular cartilage regeneration by promoting cell proliferation and inhibiting extracellular matrix metabolism. Front Cell Dev Biol, 2021, 9: 630678.
[45]	Liang Z, Damianou A, Di Daniel E, et al. Inflammasome activation controlled by the interplay between post-translational modifications: Emerging drug target opportunities. Cell Commun Signal, 2021, 19(1): 23.

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[1]	Swanson K V, Deng M, Ting J P. The NLRP3 inflammasome: Molecular activation and regulation to therapeutics. Nat Rev Immunol, 2019, 19(8): 477-489.
[2]	Hara H, Tsuchiya K, Kawamura I, et al. Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat Immunol, 2013, 14(12): 1247-1255.
[3]	Martinon F, Burns K, Tschopp J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell, 2002, 10(2): 417-426.
[4]	He W T, Wan H, Hu L, et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res, 2015, 25(12): 1285-1298.
[5]	Shi J, Zhao Y, Wang K, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature, 2015, 526(7575): 660-665.
[6]	Kelley N, Jeltema D, Duan Y, et al. The NLRP3 inflammasome: An overview of mechanisms of activation and regulation. Int J Mol Sci, 2019, 20(13): 3328.
[7]	Gong T, Jiang W, Zhou R. Control of inflammasome activation by phosphorylation. Trends Biochem Sci, 2018, 43(9): 685-699.
[8]	Song N, Li T. Regulation of NLRP3 inflammasome by phosphorylation. Front Immunol, 2018, 9: 2305.
[9]	Ubersax J A, Ferrell J E, Jr. Mechanisms of specificity in protein phosphorylation. Nat Rev Mol Cell Biol, 2007, 8(7): 530-541.
[10]	Ardito F, Giuliani M, Perrone D, et al. The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review). Int J Mol Med, 2017, 40(2): 271-280.
[11]	He Y, Zeng M Y, Yang D, et al. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature, 2016, 530(7590): 354-357.
[12]	Schmid-Burgk J L, Chauhan D, Schmidt T, et al. A Genome-wide CRISPR (clustered regularly interspaced short palindromic repeats) screen identifies NEK7 as an essential component of NLRP3 inflammasome activation. J Biol Chem, 2016, 291(1): 103-109.
[13]	Shi H, Wang Y, Li X, et al. NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat Immunol, 2016, 17(3): 250-258.
[14]	Spalinger M R, Kasper S, Gottier C, et al. NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN22. J Clin Invest, 2016, 126(5): 1783-1800.
[15]	Spalinger M R, Lang S, Gottier C, et al. PTPN22 regulates NLRP3-mediated IL1B secretion in an autophagy-dependent manner. Autophagy, 2017, 13(9): 1590-1601.
[16]	Xiao Y, Tang J, Lin G, et al. Tyrosine phosphorylation of NLRP3 by Src family protein tyrosine kinase Lyn suppresses NLRP3 inflammasome activation. J Immunol,2020,204:68.19.
[17]	Shio M T, Eisenbarth S C, Savaria M, et al. Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. PLoS Pathog, 2009, 5(8): e1000559.
[18]	Becker C E, Creagh E M, O’Neill L A. Rab39a binds caspase-1 and is required for caspase-1-dependent interleukin-1beta secretion. J Biol Chem, 2009, 284(50): 34531-34537.
[19]	Mortimer L, Moreau F, MacDonald J A, et al. NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations. Nat Immunol, 2016, 17(10): 1176-1186.
[20]	Guo C, Xie S, Chi Z, et al. Bile Acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity, 2016, 45(4): 802-816.
[21]	Zhang Z, Meszaros G, He W T, et al. Protein kinase D at the Golgi controls NLRP3 inflammasome activation. J Exp Med, 2017, 214(9): 2671-2693.
[22]	Dufies O, Doye A, Courjon J, et al. Escherichia coli Rho GTPase-activating toxin CNF1 mediates NLRP3 inflammasome activation via p21-activated kinases-1/2 during bacteraemia in mice. Nat Microbiol, 2021, 6(3): 401-412.
[23]	Ting J P, Lovering R C, Alnemri E S, et al. The NLR gene family: A standard nomenclature. Immunity, 2008, 28(3): 285-287.
[24]	Stutz A, Kolbe C C, Stahl R, et al. NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain. J Exp Med, 2017, 214(6): 1725-1736.
[25]	Huang Y, Wang H, Hao Y, et al. Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity. Nat Cell Biol, 2020, 22(6): 716-727.
[26]	Zhang A, Xing J, Xia T, et al. EphA2 phosphorylates NLRP3 and inhibits inflammasomes in airway epithelial cells. EMBO Rep, 2020, 21(7): e49666.
[27]	Song N, Liu Z S, Xue W, et al. NLRP3 phosphorylation is an essential priming event for inflammasome activation. Mol Cell, 2017, 68(1): 185-197.e6.
[28]	Ren G, Zhang X, Xiao Y, et al. ABRO1 promotes NLRP3 inflammasome activation through regulation of NLRP3 deubiquitination. EMBO J, 2019, 38(6):e100376.
[29]	Martin B N, Wang C, Willette-Brown J, et al. IKKalpha negatively regulates ASC-dependent inflammasome activation. Nat Commun, 2014, 5: 4977.
[30]	Mambwe B, Neo K, Javanmard Khameneh H, et al. Tyrosine dephosphorylation of ASC modulates the activation of the NLRP3 and AIM2 inflammasomes. Front Immunol, 2019, 10: 1556.
[31]	Chung I C, OuYang C N, Yuan S N, et al. Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis. Sci Rep, 2016, 6: 36214.
[32]	Gavrilin M A, Prather E R, Vompe A D, et al. cAbl kinase regulates inflammasome activation and pyroptosis via ASC phosphorylation. J Immunol, 2021, 206(6):1329-1336.
[33]	Okada M, Matsuzawa A, Yoshimura A, et al. The lysosome rupture-activated TAK1-JNK pathway regulates NLRP3 inflammasome activation. J Biol Chem, 2014, 289(47): 32926-32936.
[34]	Basak C, Pathak S K, Bhattacharyya A, et al. NF-kappaB- and C/EBPbeta-driven interleukin-1beta gene expression and PAK1-mediated caspase-1 activation play essential roles in interleukin-1beta release from Helicobacter pylori lipopolysaccharide-stimulated macrophages. J Biol Chem, 2005, 280(6): 4279-4288.
[35]	Yang X D, Li W, Zhang S, et al. PLK4 deubiquitination by Spata2-CYLD suppresses NEK7-mediated NLRP3 inflammasome activation at the centrosome. EMBO J, 2020, 39(2): e102201.
[36]	Samir P, Kesavardhana S, Patmore D M, et al. DDX3X acts as a live-or-die checkpoint in stressed cells by regulating NLRP3 inflammasome. Nature, 2019, 573(7775): 590-594.
[37]	Gu L, Fullam A, Brennan R, et al. Human DEAD box helicase 3 couples IkappaB kinase epsilon to interferon regulatory factor 3 activation. Mol Cell Biol, 2013, 33(10): 2004-2015.
[38]	Ito M, Shichita T, Okada M, et al. Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat Commun, 2015, 6: 7360.
[39]	Liu X, Pichulik T, Wolz O O, et al. Human NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase. J Allergy Clin Immunol, 2017, 140(4): 1054-1067.e10.
[40]	Weber A N R. Targeting the NLRP3 inflammasome via BTK. Front Cell Dev Biol, 2021, 9: 630479.
[41]	Purvis G S D, Collino M, Aranda-Tavio H, et al. Inhibition of Bruton’s TK regulates macrophage NF-kappaB and NLRP3 inflammasome activation in metabolic inflammation. Br J Pharmacol, 2020, 177(19): 4416-4432.
[42]	O’Riordan C E, Purvis G S D, Collotta D, et al. Bruton’styrosine kinase inhibition attenuates the cardiac dysfunction caused by cecal ligation and puncture in mice. Front Immunol, 2019, 10: 2129.
[43]	Hussein M, Chai D C, Kyama C M, et al. c-Jun NH2-terminal kinase inhibitor bentamapimod reduces induced endometriosis in baboons: An assessor-blind placebo-controlled randomized study. Fertil Steril, 2016, 105(3): 815-824.e5.
[44]	Zhang P, Liu Y, Jia L, et al. SP600125, a JNK-specific inhibitor, regulates in vitro auricular cartilage regeneration by promoting cell proliferation and inhibiting extracellular matrix metabolism. Front Cell Dev Biol, 2021, 9: 630678.
[45]	Liang Z, Damianou A, Di Daniel E, et al. Inflammasome activation controlled by the interplay between post-translational modifications: Emerging drug target opportunities. Cell Commun Signal, 2021, 19(1): 23.

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