A Preliminary Study of KAT2A on CGAS-related Immunity in Inflammation Amplification of Systemic Lupus Erythematosus

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2021 Oct 31

PMID 34718330

Citations 4

Authors

Youzhou Tang

Xinyu Li

Yafang Wei

Yongchao Sun

Yeyi Yang

Xianming Zhang

Zhihao Gao

Jishi Liu

Quan Zhuang

Affiliations

Soon will be listed here.

Abstract

Previous studies demonstrated that cGAS pathway is related to the inflammation amplification in a variety of autoimmune diseases. Lysine acetyltransferase family (KATs) can regulate the nuclear transcription or cytoplasmic activation of cGAS through different mechanisms. However, its role and related immunity patterns in systemic lupus erythematosus (SLE) have not been explored. In this study, RNA-seq and scRNA-seq profiling were performed for peripheral blood mononuclear cells (PBMCs) from patients with SLE. R packages were used for bioinformatic analysis. Cell culture, RT-PCR, western blotting, immunofluorescence, immunohistochemistry, and ELISA were used to explore gene expression in vitro or clinical specimens. Plasmid transfection and mass spectrometry were used to detect protein modifications. Eight acetyltransferase and deacetylase family members with significantly differential expression in SLE were found. Among them, KAT2A was abnormally upregulated and positively correlated with disease activity index. Further, KAT2A-cGAS pathway was aberrantly expressed in specific immune cell subsets in SLE. In vitro studies showed KAT2A modulated cGAS through increasing expression and post-translational modification. Our research provides novel insights for accurately positioning specific immune-cell subgroups in which KAT2A-cGAS reaction mainly works and KAT2A regulation patterns.

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References

Paolinelli R, Mendoza-Maldonado R, Cereseto A, Giacca M . Acetylation by GCN5 regulates CDC6 phosphorylation in the S phase of the cell cycle. Nat Struct Mol Biol. 2009; 16(4):412-20. DOI: 10.1038/nsmb.1583. View

Gao D, Li T, Li X, Chen X, Li Q, Wight-Carter M . Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc Natl Acad Sci U S A. 2015; 112(42):E5699-705. PMC: 4620884. DOI: 10.1073/pnas.1516465112. View

Kumar V . A STING to inflammation and autoimmunity. J Leukoc Biol. 2019; 106(1):171-185. DOI: 10.1002/JLB.4MIR1018-397RR. View

Guthridge J, Lu R, Tran L, Arriens C, Aberle T, Kamp S . Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study. EClinicalMedicine. 2020; 20():100291. PMC: 7058913. DOI: 10.1016/j.eclinm.2020.100291. View

Sandoz J, Nagy Z, Catez P, Caliskan G, Geny S, Renaud J . Functional interplay between TFIIH and KAT2A regulates higher-order chromatin structure and class II gene expression. Nat Commun. 2019; 10(1):1288. PMC: 6426930. DOI: 10.1038/s41467-019-09270-2. View

Kato Y, Park J, Takamatsu H, Konaka H, Aoki W, Aburaya S . Apoptosis-derived membrane vesicles drive the cGAS-STING pathway and enhance type I IFN production in systemic lupus erythematosus. Ann Rheum Dis. 2018; 77(10):1507-1515. PMC: 6161667. DOI: 10.1136/annrheumdis-2018-212988. View

Zhang X, Bai X, Chen Z . Structures and Mechanisms in the cGAS-STING Innate Immunity Pathway. Immunity. 2020; 53(1):43-53. DOI: 10.1016/j.immuni.2020.05.013. View

Fournier M, Orpinell M, Grauffel C, Scheer E, Garnier J, Ye T . KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification. Nat Commun. 2016; 7:13227. PMC: 5095585. DOI: 10.1038/ncomms13227. View

Ouyang C, Mu J, Lu Q, Li J, Zhu H, Wang Q . Autophagic degradation of KAT2A/GCN5 promotes directional migration of vascular smooth muscle cells by reducing TUBA/α-tubulin acetylation. Autophagy. 2019; 16(10):1753-1770. PMC: 8386598. DOI: 10.1080/15548627.2019.1707488. View

10.

Lou H, Wojciak-Stothard B, Ruseva M, Cook H, Kelleher P, Pickering M . Autoantibody-dependent amplification of inflammation in SLE. Cell Death Dis. 2020; 11(9):729. PMC: 7481301. DOI: 10.1038/s41419-020-02928-6. View

11.

Chimenti F, Bizzarri B, Maccioni E, Secci D, Bolasco A, Chimenti P . A novel histone acetyltransferase inhibitor modulating Gcn5 network: cyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl)hydrazone. J Med Chem. 2008; 52(2):530-6. DOI: 10.1021/jm800885d. View

12.

Kassianos A, Wang X, Sampangi S, Muczynski K, Healy H, Wilkinson R . Increased tubulointerstitial recruitment of human CD141(hi) CLEC9A(+) and CD1c(+) myeloid dendritic cell subsets in renal fibrosis and chronic kidney disease. Am J Physiol Renal Physiol. 2013; 305(10):F1391-401. DOI: 10.1152/ajprenal.00318.2013. View

13.

Soni C, Perez O, Voss W, Pucella J, Serpas L, Mehl J . Plasmacytoid Dendritic Cells and Type I Interferon Promote Extrafollicular B Cell Responses to Extracellular Self-DNA. Immunity. 2020; 52(6):1022-1038.e7. PMC: 7306002. DOI: 10.1016/j.immuni.2020.04.015. View

14.

Helmlinger D, Papai G, Devys D, Tora L . What do the structures of GCN5-containing complexes teach us about their function?. Biochim Biophys Acta Gene Regul Mech. 2020; 1864(2):194614. DOI: 10.1016/j.bbagrm.2020.194614. View

15.

Song Z, Lin H, Yi X, Guo W, Hu M, Shu H . KAT5 acetylates cGAS to promote innate immune response to DNA virus. Proc Natl Acad Sci U S A. 2020; 117(35):21568-21575. PMC: 7474609. DOI: 10.1073/pnas.1922330117. View

16.

Nehar-Belaid D, Hong S, Marches R, Chen G, Bolisetty M, Baisch J . Mapping systemic lupus erythematosus heterogeneity at the single-cell level. Nat Immunol. 2020; 21(9):1094-1106. PMC: 7442743. DOI: 10.1038/s41590-020-0743-0. View

17.

Thim-Uam A, Prabakaran T, Tansakul M, Makjaroen J, Wongkongkathep P, Chantaravisoot N . STING Mediates Lupus via the Activation of Conventional Dendritic Cell Maturation and Plasmacytoid Dendritic Cell Differentiation. iScience. 2020; 23(9):101530. PMC: 7502826. DOI: 10.1016/j.isci.2020.101530. View

18.

Dutertre C, Becht E, Irac S, Khalilnezhad A, Narang V, Khalilnezhad S . Single-Cell Analysis of Human Mononuclear Phagocytes Reveals Subset-Defining Markers and Identifies Circulating Inflammatory Dendritic Cells. Immunity. 2019; 51(3):573-589.e8. DOI: 10.1016/j.immuni.2019.08.008. View

19.

Menon M, Blair P, Isenberg D, Mauri C . A Regulatory Feedback between Plasmacytoid Dendritic Cells and Regulatory B Cells Is Aberrant in Systemic Lupus Erythematosus. Immunity. 2016; 44(3):683-697. PMC: 4803914. DOI: 10.1016/j.immuni.2016.02.012. View

20.

Jing Y, Dai X, Yang L, Kang D, Jiang P, Li N . STING couples with PI3K to regulate actin reorganization during BCR activation. Sci Adv. 2020; 6(17):eaax9455. PMC: 7176427. DOI: 10.1126/sciadv.aax9455. View