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Current Stem Cell Research & Therapy

Editor-in-Chief

ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Review Article

Effector Proteins of Type IV Secretion System: Weapons of Brucella Used to Fight Against Host Immunity

Author(s): Min Zheng, Ruiqi Lin, Jinying Zhu, Qiao Dong, Jingjing Chen, Pengfei Jiang, Huan Zhang*, Jinling Liu* and Zeliang Chen*

Volume 19, Issue 2, 2024

Published on: 13 March, 2023

Page: [145 - 153] Pages: 9

DOI: 10.2174/1574888X18666230222124529

Price: $65

Abstract

Brucella is an intracellular bacterial pathogen capable of long-term persistence in the host, resulting in chronic infections in livestock and wildlife. The type IV secretion system (T4SS) is an important virulence factor of Brucella and is composed of 12 protein complexes encoded by the VirB operon. T4SS exerts its function through its secreted 15 effector proteins. The effector proteins act on important signaling pathways in host cells, inducing host immune responses and promoting the survival and replication of Brucella in host cells to promote persistent infection. In this article, we describe the intracellular circulation of Brucella-infected cells and survey the role of Brucella VirB T4SS in regulating inflammatory responses and suppressing host immune responses during infection. In addition, the important mechanisms of these 15 effector proteins in resisting the host immune response during Brucella infection are elucidated. For example, VceC and VceA assist in achieving sustained survival of Brucella in host cells by affecting autophagy and apoptosis. BtpB, together with BtpA, controls the activation of dendritic cells during infection, induces inflammatory responses, and controls host immunity. This article reviews the effector proteins secreted by Brucella T4SS and their involvement in immune responses, which can provide a reliable theoretical basis for the subsequent mechanism of hijacking the host cell signaling pathway by bacteria and contribute to the development of better vaccines to effectively treat Brucella bacterial infection.

Graphical Abstract

[1]
Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV. The new global map of human brucellosis. Lancet Infect Dis 2006; 6(2): 91-9.
[http://dx.doi.org/10.1016/S1473-3099(06)70382-6] [PMID: 16439329]
[2]
Al Dahouk S, Neubauer H, Hensel A, et al. Changing epidemiology of human brucellosis, Germany, 1962-2005. Emerg Infect Dis 2007; 13(12): 1895-900.
[http://dx.doi.org/10.3201/eid1312.070527] [PMID: 18258041]
[3]
von Bargen K, Gorvel JP, Salcedo SP. Internal affairs: investigating the Brucella intracellular lifestyle. FEMS Microbiol Rev 2012; 36(3): 533-62.
[http://dx.doi.org/10.1111/j.1574-6976.2012.00334.x] [PMID: 22373010]
[4]
Porte F, Naroeni A, Ouahrani-Bettache S, Liautard JP. Role of the Brucella suis lipopolysaccharide O antigen in phagosomal genesis and in inhibition of phagosome-lysosome fusion in murine macrophages. Infect Immun 2003; 71(3): 1481-90.
[http://dx.doi.org/10.1128/IAI.71.3.1481-1490.2003] [PMID: 12595466]
[5]
Elfaki MG, Alaidan AA, Al-Hokail AA. Host response to Brucella infection: Review and future perspective. J Infect Dev Ctries 2015; 9(7): 697-701.
[http://dx.doi.org/10.3855/jidc.6625] [PMID: 26230118]
[6]
Pappas G. The changing Brucella ecology: Novel reservoirs, new threats. Int J Antimicrob Agents 2010; 36 (Suppl. 1): S8-S11.
[http://dx.doi.org/10.1016/j.ijantimicag.2010.06.013] [PMID: 20696557]
[7]
Seleem MN, Boyle SM, Sriranganathan N. Brucella: A pathogen without classic virulence genes. Vet Microbiol 2008; 129(1-2): 1-14.
[http://dx.doi.org/10.1016/j.vetmic.2007.11.023] [PMID: 18226477]
[8]
Seleem MN, Jain N, Pothayee N, Ranjan A, Riffle JS, Sriranganathan N. Targeting Brucella melitensis with polymeric nanoparticles containing streptomycin and doxycycline. FEMS Microbiol Lett 2009; 294(1): 24-31.
[http://dx.doi.org/10.1111/j.1574-6968.2009.01530.x] [PMID: 19493005]
[9]
Fretin D, Fauconnier A, Köhler S, et al. The sheathed flagellum of Brucella melitensis is involved in persistence in a murine model of infection. Cell Microbiol 2005; 7(5): 687-98.
[http://dx.doi.org/10.1111/j.1462-5822.2005.00502.x] [PMID: 15839898]
[10]
Ficht T. Brucella taxonomy and evolution. Future Microbiol 2010; 5(6): 859-66.
[http://dx.doi.org/10.2217/fmb.10.52] [PMID: 20521932]
[11]
Carmichael LE, Bruner DW. Characteristics of a newly-recognized species of Brucella responsible for infectious canine abortions. Cornell Vet 1968; 48(4): 579-92.
[PMID: 5693645]
[12]
Buddle MB. Studies on Brucella ovis (n.sp.), a cause of genital disease of sheep in new Zealand and Australia. J Hyg (Lond) 1956; 54(3): 351-64.
[http://dx.doi.org/10.1017/S0022172400044612] [PMID: 13367402]
[13]
Stoenner HG, Lackman DB. A new species of Brucella isolated from the desert wood rat, Neotoma lepida Thomas. Am J Vet Res 1957; 18(69): 947-51.
[PMID: 13470254]
[14]
Al Dahouk S, Köhler S, Occhialini A, et al. Brucella spp. of amphibians comprise genomically diverse motile strains competent for replication in macrophages and survival in mammalian hosts. Sci Rep 2017; 7(1): 44420.
[http://dx.doi.org/10.1038/srep44420] [PMID: 28300153]
[15]
Głowacka P, Żakowska D, Naylor K, Niemcewicz M, Bielawska-Drózd A. Brucella - Virulence Factors, Pathogenesis and Treatment. Pol J Microbiol 2018; 67(2): 151-61.
[http://dx.doi.org/10.21307/pjm-2018-029] [PMID: 30015453]
[16]
Al Dahouk S, Flèche PL, Nöckler K, et al. Evaluation of Brucella MLVA typing for human brucellosis. J Microbiol Methods 2007; 69(1): 137-45.
[http://dx.doi.org/10.1016/j.mimet.2006.12.015] [PMID: 17261338]
[17]
de Figueiredo P, Ficht TA, Rice-Ficht A, Rossetti CA, Adams LG. Pathogenesis and immunobiology of brucellosis: Review of Brucella-host interactions. Am J Pathol 2015; 185(6): 1505-17.
[http://dx.doi.org/10.1016/j.ajpath.2015.03.003] [PMID: 25892682]
[18]
Rajashekara G, Eskra L, Mathison A, et al. Brucella: Functional genomics and host-pathogen interactions. Anim Health Res Rev 2006; 7(1-2): 1-11.
[http://dx.doi.org/10.1017/S146625230700117X] [PMID: 17389050]
[19]
Pizarro-Cerdá J, Méresse S, Parton RG, et al. Brucella abortus transits through the autophagic pathway and replicates in the endoplasmic reticulum of nonprofessional phagocytes. Infect Immun 1998; 66(12): 5711-24.
[http://dx.doi.org/10.1128/IAI.66.12.5711-5724.1998] [PMID: 9826346]
[20]
De Bolle X, Crosson S, Matroule JY, Letesson JJ. Brucella abortus cell cycle and infection are coordinated. Trends Microbiol 2015; 23(12): 812-21.
[http://dx.doi.org/10.1016/j.tim.2015.09.007] [PMID: 26497941]
[21]
Starr T, Ng TW, Wehrly TD, Knodler LA, Celli J. Brucella intracellular replication requires trafficking through the late endosomal/lysosomal compartment. Traffic 2008; 9(5): 678-94.
[http://dx.doi.org/10.1111/j.1600-0854.2008.00718.x] [PMID: 18266913]
[22]
Celli J, de Chastellier C, Franchini DM, Pizarro-Cerda J, Moreno E, Gorvel JP. Brucella evades macrophage killing via VirB-dependent sustained interactions with the endoplasmic reticulum. J Exp Med 2003; 198(4): 545-56.
[http://dx.doi.org/10.1084/jem.20030088] [PMID: 12925673]
[23]
Boschiroli ML, Ouahrani-Bettache S, Foulongne V, et al. The Brucella suis virB operon is induced intracellularly in macrophages. Proc Natl Acad Sci USA 2002; 99(3): 1544-9.
[http://dx.doi.org/10.1073/pnas.032514299] [PMID: 11830669]
[24]
Starr T, Child R, Wehrly TD, et al. Selective subversion of autophagy complexes facilitates completion of the Brucella intracellular cycle. Cell Host Microbe 2012; 11(1): 33-45.
[http://dx.doi.org/10.1016/j.chom.2011.12.002] [PMID: 22264511]
[25]
Hong PC, Tsolis RM, Ficht TA. Identification of genes required for chronic persistence of Brucella abortus in mice. Infect Immun 2000; 68(7): 4102-7.
[http://dx.doi.org/10.1128/IAI.68.7.4102-4107.2000] [PMID: 10858227]
[26]
Ke Y, Wang Y, Li W, Chen Z. Type IV secretion system of Brucella spp. and its effectors. Front Cell Infect Microbiol 2015; 5: 72.
[http://dx.doi.org/10.3389/fcimb.2015.00072] [PMID: 26528442]
[27]
Hashemifar I, Yadegar A, Jazi FM, Amirmozafari N. Molecular prevalence of putative virulence-associated genes in Brucella melitensis and Brucella abortus isolates from human and livestock specimens in Iran. Microb Pathog 2017; 105: 334-9.
[http://dx.doi.org/10.1016/j.micpath.2017.03.007] [PMID: 28284850]
[28]
López-Santiago R, Sánchez-Argáez AB, De Alba-Núñez LG, Baltierra-Uribe SL, Moreno-Lafont MC. Immune response to mucosal Brucella infection. Front Immunol 2019; 10: 1759.
[http://dx.doi.org/10.3389/fimmu.2019.01759] [PMID: 31481953]
[29]
Marim FM, Franco MMC, Gomes MTR, Miraglia MC, Giambartolomei GH, Oliveira SC. The role of NLRP3 and AIM2 in inflammasome activation during Brucella abortus infection. Semin Immunopathol 2017; 39(2): 215-23.
[http://dx.doi.org/10.1007/s00281-016-0581-1] [PMID: 27405866]
[30]
Jiménez de Bagüés MP, Terraza A, Gross A, Dornand J. Different responses of macrophages to smooth and rough Brucella spp.: Relationship to virulence. Infect Immun 2004; 72(4): 2429-33.
[http://dx.doi.org/10.1128/IAI.72.4.2429-2433.2004] [PMID: 15039375]
[31]
Alvarez-Martinez CE, Christie PJ. Biological diversity of prokaryotic type IV secretion systems. Microbiol Mol Biol Rev 2009; 73(4): 775-808.
[http://dx.doi.org/10.1128/MMBR.00023-09] [PMID: 19946141]
[32]
Xiong X, Li B, Zhou Z, et al. The VirB system plays a crucial role in Brucella intracellular infection. Int J Mol Sci 2021; 22(24): 13637.
[http://dx.doi.org/10.3390/ijms222413637] [PMID: 34948430]
[33]
Lacerda TLS, Salcedo SP, Gorvel JP. Brucella T4SS: The VIP pass inside host cells. Curr Opin Microbiol 2013; 16(1): 45-51.
[http://dx.doi.org/10.1016/j.mib.2012.11.005] [PMID: 23318140]
[34]
Fugier E, Salcedo SP, de Chastellier C, et al. The glyceraldehyde-3-phosphate dehydrogenase and the small GTPase Rab 2 are crucial for Brucella replication. PLoS Pathog 2009; 5(6): e1000487.
[http://dx.doi.org/10.1371/journal.ppat.1000487] [PMID: 19557163]
[35]
de Jong MF, Sun YH, den Hartigh AB, van Dijl JM, Tsolis RM. Identification of VceA and VceC, two members of the VjbR regulon that are translocated into macrophages by the Brucella type IV secretion system. Mol Microbiol 2008; 70(6): 1378-96.
[http://dx.doi.org/10.1111/j.1365-2958.2008.06487.x] [PMID: 19019140]
[36]
de Barsy M, Jamet A, Filopon D, et al. Identification of a Brucella spp. secreted effector specifically interacting with human small GTPase Rab2. Cell Microbiol 2011; 13(7): 1044-58.
[http://dx.doi.org/10.1111/j.1462-5822.2011.01601.x] [PMID: 21501366]
[37]
Marchesini MI, Herrmann CK, Salcedo SP, Gorvel JP, Comerci DJ. In search of Brucella abortus type IV secretion substrates: Screening and identification of four proteins translocated into host cells through VirB system. Cell Microbiol 2011; 13(8): 1261-74.
[http://dx.doi.org/10.1111/j.1462-5822.2011.01618.x] [PMID: 21707904]
[38]
Myeni S, Child R, Ng TW, et al. Brucella modulates secretory trafficking via multiple type IV secretion effector proteins. PLoS Pathog 2013; 9(8): e1003556.
[http://dx.doi.org/10.1371/journal.ppat.1003556] [PMID: 23950720]
[39]
Döhmer PH, Valguarnera E, Czibener C, Ugalde JE. Identification of a type IV secretion substrate of Brucella abortus that participates in the early stages of intracellular survival. Cell Microbiol 2014; 16(3): 396-410.
[http://dx.doi.org/10.1111/cmi.12224] [PMID: 24119283]
[40]
Salcedo SP, Marchesini MI, Degos C, et al. BtpB, a novel Brucella TIR-containing effector protein with immune modulatory functions. Front Cell Infect Microbiol 2013; 3: 28.
[http://dx.doi.org/10.3389/fcimb.2013.00028] [PMID: 23847770]
[41]
Zhang J, Li M, Li Z, et al. Deletion of the type IV secretion system effector VceA promotes autophagy and inhibits apoptosis in brucella-infected human trophoblast cells. Curr Microbiol 2019; 76(4): 510-9.
[http://dx.doi.org/10.1007/s00284-019-01651-6] [PMID: 30805699]
[42]
Haas IG. BiP (GRP78), an essential hsp70 resident protein in the endoplasmic reticulum. Experientia 1994; 50(11-12): 1012-20.
[http://dx.doi.org/10.1007/BF01923455] [PMID: 7988659]
[43]
Todd DJ, Lee AH, Glimcher LH. The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol 2008; 8(9): 663-74.
[http://dx.doi.org/10.1038/nri2359] [PMID: 18670423]
[44]
Roux CM, Rolán HG, Santos RL, et al. Brucella requires a functional Type IV secretion system to elicit innate immune responses in mice. Cell Microbiol 2007; 9(7): 1851-69.
[http://dx.doi.org/10.1111/j.1462-5822.2007.00922.x] [PMID: 17441987]
[45]
Pahl HL, Baeuerle PA. A novel signal transduction pathway from the endoplasmic reticulum to the nucleus is mediated by transcription factor NF-kappa B. EMBO J 1995; 14(11): 2580-8.
[http://dx.doi.org/10.1002/j.1460-2075.1995.tb07256.x] [PMID: 7781611]
[46]
Pahl HL, Baeuerle PA. Expression of influenza virus hemagglutinin activates transcription factor NF-kappa B. J Virol 1995; 69(3): 1480-4.
[http://dx.doi.org/10.1128/jvi.69.3.1480-1484.1995] [PMID: 7853480]
[47]
de Jong MF, Starr T, Winter MG, et al. Sensing of bacterial type IV secretion via the unfolded protein response. MBio 2013; 4(1): e00418-12.
[http://dx.doi.org/10.1128/mBio.00418-12] [PMID: 23422410]
[48]
Taguchi Y, Imaoka K, Kataoka M, et al. Yip1A, a novel host factor for the activation of the IRE1 pathway of the unfolded protein response during Brucella infection. PLoS Pathog 2015; 11(3): e1004747.
[http://dx.doi.org/10.1371/journal.ppat.1004747] [PMID: 25742138]
[49]
Keestra-Gounder AM, Byndloss MX, Seyffert N, et al. NOD1 and NOD2 signalling links ER stress with inflammation. Nature 2016; 532(7599): 394-7.
[http://dx.doi.org/10.1038/nature17631] [PMID: 27007849]
[50]
Zhi F, Zhou D, Bai F, et al. VceC Mediated ire1 pathway and inhibited chop-induced apoptosis to support Brucella replication in goat trophoblast cells. Int J Mol Sci 2019; 20(17): 4104.
[http://dx.doi.org/10.3390/ijms20174104] [PMID: 31443507]
[51]
Byndloss MX, Tsai AY, Walker GT, et al. Brucella abortus infection of placental trophoblasts triggers endoplasmic reticulum stress-mediated cell death and fetal loss via Type IV secretion system-dependent activation of CHOP. MBio 2019; 10(4): e01538-19.
[http://dx.doi.org/10.1128/mBio.01538-19] [PMID: 31337727]
[52]
Herrou J, Crosson S. Molecular structure of the Brucella abortus metalloprotein RicA, a Rab2-binding virulence effector. Biochemistry 2013; 52(50): 9020-8.
[http://dx.doi.org/10.1021/bi401373r] [PMID: 24251537]
[53]
Nkengfac B, Pouyez J, Bauwens E, et al. Structural analysis of Brucella abortus RicA substitutions that do not impair interaction with human Rab2 GTPase. BMC Biochem 2012; 13(1): 16.
[http://dx.doi.org/10.1186/1471-2091-13-16] [PMID: 22892012]
[54]
Smith EP, Cotto-Rosario A, Borghesan E, Held K, Miller CN, Celli J. Epistatic interplay between type iv secretion effectors engages the small GTPase Rab2 in the Brucella intracellular cycle. MBio 2020; 11(2): e03350-19.
[http://dx.doi.org/10.1128/mBio.03350-19] [PMID: 32234817]
[55]
de Bolle X, Letesson JJ, Gorvel JP. Small GTPases and Brucella entry into the endoplasmic reticulum. Biochem Soc Trans 2012; 40(6): 1348-52.
[http://dx.doi.org/10.1042/BST20120156] [PMID: 23176479]
[56]
Coronas-Serna JM, Louche A, Rodríguez-Escudero M, et al. The TIR-domain containing effectors BtpA and BtpB from Brucella abortus impact NAD metabolism. PLoS Pathog 2020; 16(4): e1007979.
[http://dx.doi.org/10.1371/journal.ppat.1007979] [PMID: 32298382]
[57]
Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol 2004; 17(1): 1-14.
[http://dx.doi.org/10.1093/intimm/dxh186] [PMID: 15585605]
[58]
Smith JA, Khan M, Magnani DD, et al. Brucella induces an unfolded protein response via TcpB that supports intracellular replication in macrophages. PLoS Pathog 2013; 9(12): e1003785.
[http://dx.doi.org/10.1371/journal.ppat.1003785] [PMID: 24339776]
[59]
Kaplan-Türköz B, Koelblen T, Felix C, et al. Structure of the Toll/interleukin 1 receptor (TIR) domain of the immunosuppressive Brucella effector BtpA/Btp1/TcpB. FEBS Lett 2013; 587(21): 3412-6.
[http://dx.doi.org/10.1016/j.febslet.2013.09.007] [PMID: 24076024]
[60]
Cirl C, Wieser A, Yadav M, et al. Subversion of Toll-like receptor signaling by a unique family of bacterial Toll/interleukin-1 receptor domain-containing proteins. Nat Med 2008; 14(4): 399-406.
[http://dx.doi.org/10.1038/nm1734] [PMID: 18327267]
[61]
Radhakrishnan GK, Yu Q, Harms JS, Splitter GA. Brucella tir domain-containing protein mimics properties of the toll-like receptor adaptor protein TIRAP. J Biol Chem 2009; 284(15): 9892-8.
[http://dx.doi.org/10.1074/jbc.M805458200] [PMID: 19196716]
[62]
Salcedo SP, Marchesini MI, Lelouard H, et al. Brucella control of dendritic cell maturation is dependent on the TIR-containing protein Btp1. PLoS Pathog 2008; 4(2): e21-1.
[http://dx.doi.org/10.1371/journal.ppat.0040021] [PMID: 18266466]
[63]
Sengupta D, Koblansky A, Gaines J, et al. Subversion of innate immune responses by Brucella through the targeted degradation of the TLR signaling adapter, MAL. J Immunol 2010; 184(2): 956-64.
[http://dx.doi.org/10.4049/jimmunol.0902008] [PMID: 20018612]
[64]
Li W, Ke Y, Wang Y, et al. Brucella TIR-like protein TcpB/Btp1 specifically targets the host adaptor protein MAL/TIRAP to promote infection. Biochem Biophys Res Commun 2016; 477(3): 509-14.
[http://dx.doi.org/10.1016/j.bbrc.2016.06.064] [PMID: 27311859]
[65]
Jakka P, Namani S, Murugan S, Rai N, Radhakrishnan G. The Brucella effector protein TcpB induces degradation of inflammatory caspases and thereby subverts non-canonical inflammasome activation in macrophages. J Biol Chem 2017; 292(50): 20613-27.
[http://dx.doi.org/10.1074/jbc.M117.815878] [PMID: 29061850]
[66]
Chaudhary A, Ganguly K, Cabantous S, et al. The Brucella TIR-like protein TcpB interacts with the death domain of MyD88. Biochem Biophys Res Commun 2012; 417(1): 299-304.
[http://dx.doi.org/10.1016/j.bbrc.2011.11.104] [PMID: 22155231]
[67]
Miller CN, Smith EP, Cundiff JA, et al. A Brucella Type IV Effector targets the cog tethering complex to remodel host secretory traffic and promote intracellular replication. Cell Host Microbe 2017; 22(3): 317-329.e7.
[http://dx.doi.org/10.1016/j.chom.2017.07.017] [PMID: 28844886]
[68]
Zhou Y, Bu Z, Qian J, et al. The UTP-glucose-1-phosphate uridylyltransferase of Brucella melitensis inhibits the activation of NF-κB via regulating the bacterial type IV secretion system. Int J Biol Macromol 2020; 164: 3098-104.
[http://dx.doi.org/10.1016/j.ijbiomac.2020.08.134] [PMID: 32827613]
[69]
Zhu J, Dong Q, Dong C, Zhang X, Zhang H, Chen Z. Global lysine crotonylation alterations of host cell proteins caused by Brucella effector BspF. Front Cell Infect Microbiol 2021; 10: 603457.
[http://dx.doi.org/10.3389/fcimb.2020.603457] [PMID: 33489935]
[70]
Borghesan E, Smith EP, Myeni S, Binder K, Knodler LA, Celli J. A Brucella effector modulates the Arf6-Rab8a GTPase cascade to promote intravacuolar replication. EMBO J 2021; 40(19): e107664.
[http://dx.doi.org/10.15252/embj.2021107664] [PMID: 34423453]
[71]
Marchesini MI, Morrone Seijo SM, Guaimas FF, Comerci DJA. T4SS effector targets host cell alpha-enolase contributing to Brucella abortus intracellular lifestyle. Front Cell Infect Microbiol 2016; 6: 153.
[http://dx.doi.org/10.3389/fcimb.2016.00153] [PMID: 27900285]
[72]
Arriola Benitez PC, Rey Serantes D, Herrmann CK, et al. The effector protein BPE005 from brucella abortus induces collagen deposition and matrix metalloproteinase 9 downmodulation via transforming growth factor β1 in hepatic stellate cells. Infect Immun 2016; 84(2): 598-606.
[http://dx.doi.org/10.1128/IAI.01227-15] [PMID: 26667834]
[73]
Arriola Benitez PC, Pesce Viglietti AI, Herrmann CK, et al. Brucella abortus promotes a fibrotic phenotype in hepatic stellate cells, with concomitant activation of the autophagy pathway. Infect Immun 2018; 86(1): e00522-17.
[http://dx.doi.org/10.1128/IAI.00522-17] [PMID: 28993461]
[74]
Giambartolomei GH, Delpino MV. Immunopathogenesis of hepatic brucellosis. Front Cell Infect Microbiol 2019; 9: 423.
[http://dx.doi.org/10.3389/fcimb.2019.00423] [PMID: 31956605]
[75]
Felix C, Kaplan Türköz B, Ranaldi S, et al. The Brucella TIR domain containing proteins BtpA and BtpB have a structural WxxxE motif important for protection against microtubule depolymerisation. Cell Commun Signal 2014; 12(1): 53.
[http://dx.doi.org/10.1186/s12964-014-0053-y] [PMID: 25304327]

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