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The E3 ubiquitin ligase CHIP protects against sepsis-induced myocardial dysfunction by inhibiting NF-κB-mediated inflammation via promoting ubiquitination and degradation of karyopherin-α 2

Published:November 14, 2022DOI:https://doi.org/10.1016/j.trsl.2022.11.006

      Abstract

      Cardiac dysfunction has been recognized as a major contributor to mortality in sepsis, which is closely associated with inflammatory reactions. The carboxy terminus of Hsc70-interacting protein (CHIP), a U-box E3 ubiquitin ligase, defends against cardiac injury caused by other factors, but its role in sepsis-induced cardiac dysfunction has yet to be determined. The present study was designed to investigate the effects of CHIP on cardiac dysfunction caused by sepsis and the molecular mechanisms underlying these processes. We discovered that the CHIP level decreased gradually in the heart at different time points after septic model construction. The decline in CHIP expression of LPS-stimulated cardiomyocytes was related to c-Jun activation that inhibited the transcription of CHIP. Functional biology experiments indicated that CHIP bound directly to karyopherin-α 2 (KPNA2) and promoted its degradation through polyubiquitination in cardiomyocytes. CHIP overexpression in cardiomyocytes obviously inhibited LPS-initiated release of TNF-α and IL-6 by promoting KPNA2 degradation, reducing NF-κB translocation into the nucleus. Consistent with the in vitro results, data obtained from animal experiments indicated that septic transgenic mice with heart-specific CHIP overexpression showed a weaker proinflammatory response and reduced cardiac dysfunction than septic control mice. Furthermore, we found that the therapeutic effect of compound YL-109 on cardiac dysfunction in septic mice was due to the upregulation of myocardial CHIP expression. These findings demonstrated that sepsis-initiated the activation of c-Jun suppressed CHIP transcription. CHIP directly promoted ubiquitin-mediated degradation of KPNA2, which reduced the production of proinflammatory cytokines by inhibiting the translocation of NF-κB from the cytoplasm into the nucleus in myocardium, thereby attenuating sepsis-induced cardiac dysfunction.

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      References

        • Singer M
        • Deutschman CS
        • Seymour CW
        • et al.
        The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
        Jama. 2016; 315: 801-810
        • Jayaprakash N
        • Gajic O
        • Frank RD
        • Smischney N.
        Elevated modified shock index in early sepsis is associated with myocardial dysfunction and mortality.
        J Crit Care. 2018; 43: 30-35
        • Merx MW
        • Weber C.
        Sepsis and the heart.
        Circulation. 2007; 116: 793-802
        • Walley KR.
        Sepsis-induced myocardial dysfunction.
        Curr Opin Crit Care. 2018; 24: 292-299
        • Schumacher SM
        • Naga Prasad SV
        Tumor Necrosis Factor-α in Heart Failure: an Updated Review.
        Curr Cardiol Rep. 2018; 20: 117
        • Jiang T
        • Peng D
        • Shi W
        • et al.
        IL-6/STAT3 Signaling Promotes Cardiac Dysfunction by Upregulating FUNDC1-Dependent Mitochondria-Associated Endoplasmic Reticulum Membranes Formation in Sepsis Mice.
        Front Cardiovasc Med. 2021; 8790612
        • Wang R
        • Xu Y
        • Fang Y
        • et al.
        Pathogenetic mechanisms of septic cardiomyopathy.
        J Cell Physiol. 2022; 237: 49-58
        • Murata S
        • Chiba T
        • Tanaka K.
        CHIP: a quality-control E3 ligase collaborating with molecular chaperones.
        Int J Biochem Cell Biol. 2003; 35: 572-578
        • Ballinger CA
        • Connell P
        • Wu Y
        • et al.
        Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions.
        Mol Cell Biol. 1999; 19: 4535-4545
        • Connell P
        • Ballinger CA
        • Jiang J
        • et al.
        The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins.
        Nat Cell Biol. 2001; 3: 93-96
        • Ranek MJ
        • Stachowski MJ
        • Kirk JA
        • Willis MS.
        The role of heat shock proteins and co-chaperones in heart failure.
        Philos Trans R Soc Lond B Biol Sci. 2018; 37320160530
        • Wang T
        • Wang W
        • Wang Q
        • et al.
        The E3 ubiquitin ligase CHIP in normal cell function and in disease conditions.
        Ann N Y Acad Sci. 2020; 1460: 3-10
        • Zhang C
        • Xu Z
        • He XR
        • et al.
        CHIP, a cochaperone/ubiquitin ligase that regulates protein quality control, is required for maximal cardioprotection after myocardial infarction in mice.
        Am J Physiol Heart Circ Physiol. 2005; 288: H2836-H2842
        • Ranek MJ
        • Oeing C
        • Sanchez-Hodge R
        • et al.
        CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury.
        Nat Commun. 2020; 11: 5237
        • Ali A
        • Kuo WW
        • Kuo CH
        • et al.
        E3 ligase activity of Carboxyl terminus of Hsc70 interacting protein (CHIP) in Wharton's jelly derived mesenchymal stem cells improves their persistence under hyperglycemic stress and promotes the prophylactic effects against diabetic cardiac damages.
        Bioeng Transl Med. 2021; 6: e10234
        • Wang L
        • Zhang TP
        • Zhang Y
        • et al.
        Protection against doxorubicin-induced myocardial dysfunction in mice by cardiac-specific expression of carboxyl terminus of hsp70-interacting protein.
        Sci Rep. 2016; 6: 28399
        • Mosammaparast N
        • Pemberton LF.
        Karyopherins: from nuclear-transport mediators to nuclear-function regulators.
        Trends Cell Biol. 2004; 14: 547-556
        • Fried H
        • Kutay U.
        Nucleocytoplasmic transport: taking an inventory.
        Cell Mol Life Sci. 2003; 60: 1659-1688
        • Lange A
        • Mills RE
        • Lange CJ
        • et al.
        Classical nuclear localization signals: definition, function, and interaction with importin alpha.
        J Biol Chem. 2007; 282: 5101-5105
        • Pumroy RA
        • Cingolani G.
        Diversification of importin-α isoforms in cellular trafficking and disease states.
        Biochem J. 2015; 466: 13-28
        • Liang P
        • Zhang H
        • Wang G
        • et al.
        KPNB1, XPO7 and IPO8 mediate the translocation ofNF-κB/p65 into the nucleus.
        Traffic. 2013; 14: 1132-1143
        • Cai Y
        • Shen Y
        • Gao L
        • et al.
        Karyopherin Alpha 2 Promotes the Inflammatory Response in Rat Pancreatic Acinar Cells Via Facilitating NF-κB Activation.
        Dig Dis Sci. 2016; 61: 747-757
        • Bhuripanyo K
        • Wang Y
        • Liu X
        • et al.
        Identifying the substrate proteins of U-box E3s E4B and CHIP by orthogonal ubiquitin transfer.
        Sci Adv. 2018; 4e1701393
        • Yu X
        • Wang Y
        • Yang D
        • et al.
        α(2A)-adrenergic blockade attenuates septic cardiomyopathy by increasing cardiac norepinephrine concentration and inhibiting cardiac endothelial activation.
        Sci Rep. 2018; 8: 5478
        • Jiang L
        • Li D
        • Wang C
        • et al.
        Decreased Expression of Karyopherin-α 1 is Related to the Malignant Degree of Cervical Cancer and is Critical for the Proliferation of Hela Cells.
        Pathol Oncol Res. 2022; 281610518
        • Yang D
        • Dai X
        • Xing Y
        • et al.
        Intrinsic cardiac adrenergic cells contribute to LPS-induced myocardial dysfunction.
        Commun Biol. 2022; 5: 96
        • Wang Y
        • Wang Y
        • Yang D
        • et al.
        β₁-adrenoceptor stimulation promotes LPS-induced cardiomyocyte apoptosis through activating PKA and enhancing CaMKII and IκBα phosphorylation.
        Crit Care. 2015; 19: 76
        • Liu X
        • Zhao B
        • Sun L
        • et al.
        Orthogonal ubiquitin transfer identifies ubiquitination substrates under differential control by the two ubiquitin activating enzymes.
        Nat Commun. 2017; 8: 14286
        • Kim SY
        • Hassan AHE
        • Chung KS
        • et al.
        Mosloflavone-Resveratrol Hybrid TMS-HDMF-5z Exhibits Potent In Vitro and In Vivo Anti-Inflammatory Effects Through NF-κB, AP-1, and JAK/STAT Inactivation.
        Front Pharmacol. 2022; 13857789
        • Yao C
        • Purwanti N
        • Karabasil MR
        • et al.
        Potential down-regulation of salivary gland AQP5 by LPS via cross-coupling of NF-kappaB and p-c-Jun/c-Fos.
        Am J Pathol. 2010; 177: 724-734
        • Korbecki J
        • Bajdak-Rusinek K.
        The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms.
        Inflamm Res. 2019; 68: 915-932
        • Hiyoshi H
        • Goto N
        • Tsuchiya M
        • et al.
        2-(4-Hydroxy-3-methoxyphenyl)-benzothiazole suppresses tumor progression and metastatic potential of breast cancer cells by inducing ubiquitin ligase CHIP.
        Sci Rep. 2014; 4: 7095
        • Hahmeyer M
        • da Silva-Santos JE.
        Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research.
        Cells. 2021; 10: 1844
        • Dickson K
        • Lehmann C.
        Inflammatory Response to Different Toxins in Experimental Sepsis Models.
        Int J Mol Sci. 2019; 20: 4341
        • Osuchowski MF
        • Ayala A
        • Bahrami S
        • et al.
        Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS): an international expert consensus initiative for improvement of animal modeling in sepsis.
        Infection. 2018; 46: 687-691
        • Hubbard WJ
        • Choudhry M
        • Schwacha MG
        • et al.
        Cecal ligation and puncture.
        Shock. 2005; 24: 52-57
        • Facchin BM
        • Dos Reis GO
        • Vieira GN
        • et al.
        Inflammatory biomarkers on an LPS-induced RAW 264.7 cell model: a systematic review and meta-analysis.
        Inflamm Res. 2022; 71: 741-758
        • Velthuijs N
        • Meldal B
        • Geessinck Q
        • et al.
        Integration of transcription coregulator complexes with sequence-specific DNA-binding factor interactomes.
        Biochim Biophys Acta Gene Regul Mech. 2021; 1864194749
        • Shaulian E
        • Karin M.
        AP-1 as a regulator of cell life and death.
        Nat Cell Biol. 2002; 4: E131-E136
        • McDonough H
        • Patterson C.
        CHIP: a link between the chaperone and proteasome systems.
        Cell Stress Chaperones. 2003; 8: 303-308
        • Wing CE
        • Fung HYJ
        • Chook YM.
        Karyopherin-mediated nucleocytoplasmic transport.
        Nat Rev Mol Cell Biol. 2022; 23: 307-328
        • Han Y
        • Wang X.
        The emerging roles of KPNA2 in cancer.
        Life Sci. 2020; 241117140
        • Tseng SF
        • Chang CY
        • Wu KJ
        • Teng SC.
        Importin KPNA2 is required for proper nuclear localization and multiple functions of NBS1.
        J Biol Chem. 2005; 280: 39594-39600
        • Hu Y
        • O'Boyle K
        • Auer J
        • et al.
        Multiple UBXN family members inhibit retrovirus and lentivirus production and canonical NFκΒ signaling by stabilizing IκBα.
        PLoS Pathog. 2017; 13e1006187
        • Seo J
        • Han SY
        • Seong D
        • Han HJ
        • Song J.
        Multifaceted C-terminus of HSP70-interacting protein regulates tumorigenesis via protein quality control.
        Arch Pharm Res. 2019; 42: 63-75
        • Löw-Friedrich I
        • Weisensee D
        • Mitrou P
        • Schoeppe W.
        Cytokines induce stress protein formation in cultured cardiac myocytes.
        Basic Res Cardiol. 1992; 87: 12-18
        • Meng X
        • Brown JM
        • Ao L
        • et al.
        Endotoxin induces cardiac HSP70 and resistance to endotoxemic myocardial depression in rats.
        Am J Physiol. 1996; 271 (C1316-24)
        • Martin L
        • Derwall M
        • Al Zoubi S
        • et al.
        The Septic Heart: Current Understanding of Molecular Mechanisms and Clinical Implications.
        Chest. 2019; 155: 427-437
        • Fenton KE
        • Parker MM.
        Cardiac Function and Dysfunction in Sepsis.
        Clin Chest Med. 2016; 37: 289-298
        • L'Heureux M
        • Sternberg M
        • Brath L
        • et al.
        Sepsis-Induced Cardiomyopathy: a Comprehensive Review.
        Curr Cardiol Rep. 2020; 22: 35
        • Beesley SJ
        • Weber G
        • Sarge T
        • et al.
        Septic Cardiomyopathy.
        Crit Care Med. 2018; 46: 625-634