GIV/Girdin Modulation of Microglial Activation in Ischemic Stroke: Impact of FTO-Mediated M6A Modification

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2024 Nov 19

PMID 39560901

Authors

Peng Xie

Mingyan Xia

Tingting Long

Dongfen Guo

Wenpeng Cao

Ping Sun

Wenfeng Yu

Affiliations

Soon will be listed here.

Abstract

Ischemic stroke (IS) is one of the most common causes of death in the world. The lack of effective pharmacological treatments for IS was primarily due to a lack of understanding of its pathogenesis. Gα-Interacting vesicle-associated protein (GIV/Girdin) is a multi-modular signal transducer and guanine nucleotide exchange factor that controls important signaling downstream of multiple receptors. The purpose of this study was to investigate the role of GIV in IS. In the present study, we found that GIV is highly expressed in the central nervous system (CNS). GIV protein level was decreased, while GIV transcript level was increased in the middle cerebral artery occlusion reperfusion (MCAO/R) mice model. Additionally, GIV was insensitive lipopolysaccharide (LPS) exposure. Interestingly, we found that GIV overexpression dramatically restrained microglial activation, inflammatory response, and M1 polarization in BV-2 microglia induced by oxygen-glucose deprivation and reoxygenation (OGD/R). On the contrary, GIV knockdown had the opposite impact. Mechanistically, we found that GIV activated the Wnt/β-catenin signaling pathway by interacting with DVL2 (disheveled segment polarity protein 2). Notably, mA demethylase fat mass and obesity-associated protein (FTO) decreased the N6-methyladenosine (m6A) modification-mediated increase of GIV expression and attenuated the inflammatory response in BV-2 stimulated by OGD/R. Taken together, our results demonstrate that GIV inhibited the inflammatory response via activating the Wnt/β-catenin signaling pathway which expression regulated in an FTO-mediated mA modification in IS. These results broaden our understanding of the role of the FTO-GIV axis in IS development.

References

Katan M, Luft A . Global Burden of Stroke. Semin Neurol. 2018; 38(2):208-211. DOI: 10.1055/s-0038-1649503. View

Xu X, Gao W, Li L, Hao J, Yang B, Wang T . Annexin A1 protects against cerebral ischemia-reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway. J Neuroinflammation. 2021; 18(1):119. PMC: 8140477. DOI: 10.1186/s12974-021-02174-3. View

Zhou F, Wang Y, Zhang C, Wu B . miR-19a/b-3p promotes inflammation during cerebral ischemia/reperfusion injury via SIRT1/FoxO3/SPHK1 pathway. J Neuroinflammation. 2021; 18(1):122. PMC: 8164774. DOI: 10.1186/s12974-021-02172-5. View

Voet S, Prinz M, van Loo G . Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology. Trends Mol Med. 2018; 25(2):112-123. DOI: 10.1016/j.molmed.2018.11.005. View

Jolivel V, Bicker F, Biname F, Ploen R, Keller S, Gollan R . Perivascular microglia promote blood vessel disintegration in the ischemic penumbra. Acta Neuropathol. 2014; 129(2):279-95. DOI: 10.1007/s00401-014-1372-1. View

Han B, Jiang W, Cui P, Zheng K, Dang C, Wang J . Microglial PGC-1α protects against ischemic brain injury by suppressing neuroinflammation. Genome Med. 2021; 13(1):47. PMC: 8004413. DOI: 10.1186/s13073-021-00863-5. View

Qin C, Zhou L, Ma X, Hu Z, Yang S, Chen M . Dual Functions of Microglia in Ischemic Stroke. Neurosci Bull. 2019; 35(5):921-933. PMC: 6754485. DOI: 10.1007/s12264-019-00388-3. View

Jin L, Zhu Z, Hong L, Qian Z, Wang F, Mao Z . ROS-responsive 18β-glycyrrhetic acid-conjugated polymeric nanoparticles mediate neuroprotection in ischemic stroke through HMGB1 inhibition and microglia polarization regulation. Bioact Mater. 2022; 19:38-49. PMC: 8980441. DOI: 10.1016/j.bioactmat.2022.03.040. View

Wang X, Enomoto A, Weng L, Mizutani Y, Abudureyimu S, Esaki N . Girdin/GIV regulates collective cancer cell migration by controlling cell adhesion and cytoskeletal organization. Cancer Sci. 2018; 109(11):3643-3656. PMC: 6215880. DOI: 10.1111/cas.13795. View

10.

Wang H, Misaki T, Taupin V, Eguchi A, Ghosh P, Farquhar M . GIV/girdin links vascular endothelial growth factor signaling to Akt survival signaling in podocytes independent of nephrin. J Am Soc Nephrol. 2014; 26(2):314-27. PMC: 4310647. DOI: 10.1681/ASN.2013090985. View

11.

Wang X, Wei Z, Lan T, He Y, Cheng B, Li R . CCDC88A/GIV promotes HBV replication and progeny secretion via enhancing endosomal trafficking and blocking autophagic degradation. Autophagy. 2021; 18(2):357-374. PMC: 8942511. DOI: 10.1080/15548627.2021.1934271. View

12.

Chen C, Enomoto A, Weng L, Taki T, Shiraki Y, Mii S . Complex roles of the actin-binding protein Girdin/GIV in DNA damage-induced apoptosis of cancer cells. Cancer Sci. 2020; 111(11):4303-4317. PMC: 7648047. DOI: 10.1111/cas.14637. View

13.

Enomoto A, Ping J, Takahashi M . Girdin, a novel actin-binding protein, and its family of proteins possess versatile functions in the Akt and Wnt signaling pathways. Ann N Y Acad Sci. 2006; 1086:169-84. DOI: 10.1196/annals.1377.016. View

14.

Swanson L, Katkar G, Tam J, Pranadinata R, Chareddy Y, Coates J . TLR4 signaling and macrophage inflammatory responses are dampened by GIV/Girdin. Proc Natl Acad Sci U S A. 2020; 117(43):26895-26906. PMC: 7604444. DOI: 10.1073/pnas.2011667117. View

15.

Oerum S, Meynier V, Catala M, Tisne C . A comprehensive review of m6A/m6Am RNA methyltransferase structures. Nucleic Acids Res. 2021; 49(13):7239-7255. PMC: 8287941. DOI: 10.1093/nar/gkab378. View

16.

Huang H, Weng H, Sun W, Qin X, Shi H, Wu H . Recognition of RNA N-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018; 20(3):285-295. PMC: 5826585. DOI: 10.1038/s41556-018-0045-z. View

17.

He L, Li H, Wu A, Peng Y, Shu G, Yin G . Functions of N6-methyladenosine and its role in cancer. Mol Cancer. 2019; 18(1):176. PMC: 6892141. DOI: 10.1186/s12943-019-1109-9. View

18.

Wei J, Yu X, Yang L, Liu X, Gao B, Huang B . FTO mediates LINE1 mA demethylation and chromatin regulation in mESCs and mouse development. Science. 2022; 376(6596):968-973. PMC: 9746489. DOI: 10.1126/science.abe9582. View

19.

Jin S, Li M, Chang H, Wang R, Zhang Z, Zhang J . The m6A demethylase ALKBH5 promotes tumor progression by inhibiting RIG-I expression and interferon alpha production through the IKKε/TBK1/IRF3 pathway in head and neck squamous cell carcinoma. Mol Cancer. 2022; 21(1):97. PMC: 8994291. DOI: 10.1186/s12943-022-01572-2. View

20.

Yoon K, Ringeling F, Vissers C, Jacob F, Pokrass M, Jimenez-Cyrus D . Temporal Control of Mammalian Cortical Neurogenesis by mA Methylation. Cell. 2017; 171(4):877-889.e17. PMC: 5679435. DOI: 10.1016/j.cell.2017.09.003. View