Comprehensive Review on the Novel Immunotherapy Target: Leucine-rich Repeat-containing 8A/volume-regulated Anion Channel

Overview

Journal Int J Biol Sci

Specialty Biology

Date 2024 Aug 8

PMID 39113714

Authors

Yaohua Hu

Jing Qin

Yifan Ma

Runze Yang

Xinyu Liu

Changhong Shi

Affiliations

Soon will be listed here.

Abstract

Leucine-rich repeat-containing 8A (LRRC8A) is a key component of the volume-regulated anion channel (VRAC) that influences essential homeostatic processes in various immune cells. These processes include the regulation of cell volume and membrane potential and the facilitation of the transport of organic agents used as anticancer drugs and immune-stimulating factors. Therefore, understanding the structure-function relationship of LRRC8A, exploring its physiological role in immunity, assessing its efficacy in treating diseases, and advancing the development of compounds that regulate its activity are important research frontiers. This review emphasized the emerging field of LRRC8A, outlined its structure and function, and summarized its role in immune cell development and immune cell-mediated antiviral and antitumor effects. Additionally, it explored the potential of LRRC8A as an immunotherapeutic target, offering insights into resolving persistent challenges and future research directions.

Citing Articles

Causal Effect of Fatty Fish Consumption on Influenza: Evidence From Two-Sample Mendelian Randomization.

Huang X, Xie Z, Li J, Li S J Multidiscip Healthc. 2025; 18:1123-1133.

PMID: 40026866 PMC: 11869765. DOI: 10.2147/JMDH.S511515.

References

Newton H, Gawali V, Chimote A, Lehn M, Palackdharry S, Hinrichs B . PD1 blockade enhances K channel activity, Ca signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer. J Immunother Cancer. 2020; 8(2). PMC: 7566435. DOI: 10.1136/jitc-2020-000844. View

Friard J, Laurain A, Rubera I, Duranton C . LRRC8/VRAC Channels and the Redox Balance: A Complex Relationship. Cell Physiol Biochem. 2021; 55(S1):106-118. DOI: 10.33594/000000341. View

Chen Y, Zuo X, Wei Q, Xu J, Liu X, Liu S . Upregulation of LRRC8A by mC modification-mediated mRNA stability suppresses apoptosis and facilitates tumorigenesis in cervical cancer. Int J Biol Sci. 2023; 19(2):691-704. PMC: 9830503. DOI: 10.7150/ijbs.79205. View

Zaydman M, Silva J, Cui J . Ion channel associated diseases: overview of molecular mechanisms. Chem Rev. 2012; 112(12):6319-33. PMC: 3586387. DOI: 10.1021/cr300360k. View

Wang Y, Sun Z, Ping J, Tang J, He B, Chang T . Cell volume controlled by LRRC8A-formed volume-regulated anion channels fine-tunes T cell activation and function. Nat Commun. 2023; 14(1):7075. PMC: 10625614. DOI: 10.1038/s41467-023-42817-y. View

Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q . TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020; 48(W1):W509-W514. PMC: 7319575. DOI: 10.1093/nar/gkaa407. View

Browe D, Baumgarten C . Angiotensin II (AT1) receptors and NADPH oxidase regulate Cl- current elicited by beta1 integrin stretch in rabbit ventricular myocytes. J Gen Physiol. 2004; 124(3):273-87. PMC: 2233887. DOI: 10.1085/jgp.200409040. View

Chen X, Wang L, Cao L, Li T, Li Z, Sun Y . Regulation of Anion Channel LRRC8 Volume-Regulated Anion Channels in Transport of 2'3'-Cyclic GMP-AMP and Cisplatin under Steady State and Inflammation. J Immunol. 2021; 206(9):2061-2074. DOI: 10.4049/jimmunol.2000989. View

Okada Y . Physiology of the volume-sensitive/regulatory anion channel VSOR/VRAC. Part 1: from its discovery and phenotype characterization to the molecular entity identification. J Physiol Sci. 2024; 74(1):3. PMC: 10795261. DOI: 10.1186/s12576-023-00897-x. View

10.

Chapman N, Boothby M, Chi H . Metabolic coordination of T cell quiescence and activation. Nat Rev Immunol. 2019; 20(1):55-70. DOI: 10.1038/s41577-019-0203-y. View

11.

Vaeth M, Feske S . Ion channelopathies of the immune system. Curr Opin Immunol. 2018; 52:39-50. PMC: 6004246. DOI: 10.1016/j.coi.2018.03.021. View

12.

Planells-Cases R, Lutter D, Guyader C, Gerhards N, Ullrich F, Elger D . Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs. EMBO J. 2015; 34(24):2993-3008. PMC: 4687416. DOI: 10.15252/embj.201592409. View

13.

Sorota S . Tyrosine protein kinase inhibitors prevent activation of cardiac swelling-induced chloride current. Pflugers Arch. 1995; 431(2):178-85. DOI: 10.1007/BF00410189. View

14.

Kubota K, Kim J, Sawada A, Tokimasa S, Fujisaki H, Matsuda-Hashii Y . LRRC8 involved in B cell development belongs to a novel family of leucine-rich repeat proteins. FEBS Lett. 2004; 564(1-2):147-52. DOI: 10.1016/S0014-5793(04)00332-1. View

15.

Conforti L, Petrovic M, Mohammad D, Lee S, Ma Q, Barone S . Hypoxia regulates expression and activity of Kv1.3 channels in T lymphocytes: a possible role in T cell proliferation. J Immunol. 2003; 170(2):695-702. DOI: 10.4049/jimmunol.170.2.695. View

16.

Hoffmann E, Dunham P . Membrane mechanisms and intracellular signalling in cell volume regulation. Int Rev Cytol. 1995; 161:173-262. DOI: 10.1016/s0074-7696(08)62498-5. View

17.

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu J . TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77(21):e108-e110. PMC: 6042652. DOI: 10.1158/0008-5472.CAN-17-0307. View

18.

Wu X, Yi X, Zhao B, Zhi Y, Xu Z, Cao Y . The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function. Pharmacol Res. 2023; 198:107016. DOI: 10.1016/j.phrs.2023.107016. View

19.

Jackson P, Morrison R, Strange K . The volume-sensitive organic osmolyte-anion channel VSOAC is regulated by nonhydrolytic ATP binding. Am J Physiol. 1994; 267(5 Pt 1):C1203-9. DOI: 10.1152/ajpcell.1994.267.5.C1203. View

20.

Erdogan M, Ugo D, Ines F . The role of ion channels in the relationship between the immune system and cancer. Curr Top Membr. 2023; 92:151-198. DOI: 10.1016/bs.ctm.2023.09.001. View