The RalGAPα1-RalA Signal Module Protects Cardiac Function Through Regulating Calcium Homeostasis

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Jul 25

PMID 35879328

Authors

Sangsang Zhu

Chao Quan

Ruizhen Wang

Derong Liang

Shu Su

Ping Rong

Kun Zhou

Xinyu Yang

Qiaoli Chen

Min Li

Qian Du

Jingzi Zhang

Lei Fang

Hong-Yu Wang

Shuai Chen

Affiliations

Soon will be listed here.

Abstract

Sarcoplasmic/endoplasmic reticulum calcium ATPase SERCA2 mediates calcium re-uptake from the cytosol into sarcoplasmic reticulum, and its dysfunction is a hallmark of heart failure. Multiple factors have been identified to modulate SERCA2 activity, however, its regulation is still not fully understood. Here we identify a Ral-GTPase activating protein RalGAPα1 as a critical regulator of SERCA2 in cardiomyocytes through its downstream target RalA. RalGAPα1 is induced by pressure overload, and its deficiency causes cardiac dysfunction and exacerbates pressure overload-induced heart failure. Mechanistically, RalGAPα1 regulates SERCA2 through direct interaction and its target RalA. Deletion of RalGAPα1 decreases SERCA2 activity and prolongs calcium re-uptake into sarcoplasmic reticulum. GDP-bound RalA, but not GTP-bound RalA, binds to SERCA2 and activates the pump for sarcoplasmic reticulum calcium re-uptake. Overexpression of a GDP-bound RalA mutant in the heart preserves cardiac function in a mouse model of heart failure. Our findings have therapeutic implications for treatment of heart failure.

Citing Articles

AS160 is a lipid-responsive regulator of cardiac Ca homeostasis by controlling lysophosphatidylinositol metabolism and signaling.

Su S, Quan C, Chen Q, Wang R, Du Q, Zhu S Nat Commun. 2024; 15(1):9602.

PMID: 39505896 PMC: 11542008. DOI: 10.1038/s41467-024-54031-5.

SUMMIT-FA: a new resource for improved transcriptome imputation using functional annotations.

Melton H, Zhang Z, Wu C Hum Mol Genet. 2023; 33(7):624-635.

PMID: 38129112 PMC: 10954367. DOI: 10.1093/hmg/ddad205.

References

Oatmen K, Cull E, Spinale F . Heart failure as interstitial cancer: emergence of a malignant fibroblast phenotype. Nat Rev Cardiol. 2019; 17(8):523-531. DOI: 10.1038/s41569-019-0286-y. View

Landstrom A, Dobrev D, Wehrens X . Calcium Signaling and Cardiac Arrhythmias. Circ Res. 2017; 120(12):1969-1993. PMC: 5607780. DOI: 10.1161/CIRCRESAHA.117.310083. View

Pitoulis F, Terracciano C . Heart Plasticity in Response to Pressure- and Volume-Overload: A Review of Findings in Compensated and Decompensated Phenotypes. Front Physiol. 2020; 11:92. PMC: 7031419. DOI: 10.3389/fphys.2020.00092. View

Kho C, Lee A, Hajjar R . Altered sarcoplasmic reticulum calcium cycling--targets for heart failure therapy. Nat Rev Cardiol. 2012; 9(12):717-33. PMC: 3651893. DOI: 10.1038/nrcardio.2012.145. View

Quan C, Li M, Du Q, Chen Q, Wang H, Campbell D . SPEG Controls Calcium Reuptake Into the Sarcoplasmic Reticulum Through Regulating SERCA2a by Its Second Kinase-Domain. Circ Res. 2018; 124(5):712-726. DOI: 10.1161/CIRCRESAHA.118.313916. View

Quan C, Du Q, Li M, Wang R, Ouyang Q, Su S . A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis. Nat Commun. 2020; 11(1):2186. PMC: 7198626. DOI: 10.1038/s41467-020-16116-9. View

Kho C, Lee A, Jeong D, Oh J, Chaanine A, Kizana E . SUMO1-dependent modulation of SERCA2a in heart failure. Nature. 2011; 477(7366):601-5. PMC: 3443490. DOI: 10.1038/nature10407. View

Camonis J, White M . Ral GTPases: corrupting the exocyst in cancer cells. Trends Cell Biol. 2005; 15(6):327-32. DOI: 10.1016/j.tcb.2005.04.002. View

Yan C, Theodorescu D . RAL GTPases: Biology and Potential as Therapeutic Targets in Cancer. Pharmacol Rev. 2017; 70(1):1-11. PMC: 5712631. DOI: 10.1124/pr.117.014415. View

10.

Simicek M, Lievens S, Laga M, Guzenko D, Aushev V, Kalev P . The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response. Nat Cell Biol. 2013; 15(10):1220-30. DOI: 10.1038/ncb2847. View

11.

Gentry L, Martin T, Reiner D, Der C . Ral small GTPase signaling and oncogenesis: More than just 15minutes of fame. Biochim Biophys Acta. 2014; 1843(12):2976-2988. PMC: 4201770. DOI: 10.1016/j.bbamcr.2014.09.004. View

12.

Shirakawa R, Fukai S, Kawato M, Higashi T, Kondo H, Ikeda T . Tuberous sclerosis tumor suppressor complex-like complexes act as GTPase-activating proteins for Ral GTPases. J Biol Chem. 2009; 284(32):21580-8. PMC: 2755882. DOI: 10.1074/jbc.M109.012112. View

13.

Chen X, Leto D, Xiong T, Yu G, Cheng A, Decker S . A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action. Mol Biol Cell. 2010; 22(1):141-52. PMC: 3016972. DOI: 10.1091/mbc.E10-08-0665. View

14.

Chen Q, Quan C, Xie B, Chen L, Zhou S, Toth R . GARNL1, a major RalGAP α subunit in skeletal muscle, regulates insulin-stimulated RalA activation and GLUT4 trafficking via interaction with 14-3-3 proteins. Cell Signal. 2014; 26(8):1636-48. DOI: 10.1016/j.cellsig.2014.04.012. View

15.

Chen Q, Rong P, Zhu S, Yang X, Ouyang Q, Wang H . Targeting RalGAPα1 in skeletal muscle to simultaneously improve postprandial glucose and lipid control. Sci Adv. 2019; 5(4):eaav4116. PMC: 6459767. DOI: 10.1126/sciadv.aav4116. View

16.

Skorobogatko Y, Dragan M, Cordon C, Reilly S, Hung C, Xia W . RalA controls glucose homeostasis by regulating glucose uptake in brown fat. Proc Natl Acad Sci U S A. 2018; 115(30):7819-7824. PMC: 6065037. DOI: 10.1073/pnas.1801050115. View

17.

Frangogiannis N . The extracellular matrix in myocardial injury, repair, and remodeling. J Clin Invest. 2017; 127(5):1600-1612. PMC: 5409799. DOI: 10.1172/JCI87491. View

18.

Agah R, Frenkel P, French B, Michael L, Overbeek P, Schneider M . Gene recombination in postmitotic cells. Targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo. J Clin Invest. 1997; 100(1):169-79. PMC: 508177. DOI: 10.1172/JCI119509. View

19.

Hong T, Shaw R . Cardiac T-Tubule Microanatomy and Function. Physiol Rev. 2016; 97(1):227-252. PMC: 6151489. DOI: 10.1152/physrev.00037.2015. View

20.

Yang J, Rothermel B, Vega R, Frey N, McKinsey T, Olson E . Independent signals control expression of the calcineurin inhibitory proteins MCIP1 and MCIP2 in striated muscles. Circ Res. 2000; 87(12):E61-8. DOI: 10.1161/01.res.87.12.e61. View