Coxsackievirus and adenovirus receptor explained

Coxsackievirus and adenovirus receptor (CAR) is a protein that in humans is encoded by the CXADR gene.[1] [2] [3] The protein encoded by this gene is a type I membrane receptor for group B coxsackie viruses and subgroup C adenoviruses. CAR protein is expressed in several tissues, including heart, brain, and, more generally, epithelial and endothelial cells. In cardiac muscle, CAR is localized to intercalated disc structures, which electrically and mechanically couple adjacent cardiomyocytes. CAR plays an important role in the pathogenesis of myocarditis, dilated cardiomyopathy, and in arrhythmia susceptibility following myocardial infarction or myocardial ischemia. In addition, an isoform of CAR (CAR-SIV) has been recently identified in the cytoplasm of pancreatic beta cells. It's been suggested that CAR-SIV resides in the insulin secreting granules and might be involved in the virus infection of these cells.[4]

Structure

Human CAR protein has a theoretical molecular weight of 40.0 kDa and is composed of 365 amino acids.[5] The human CAR gene (CXADR) is found on chromosome 21. Alternative splicing is known to produce at least 2 splice variants known as hCAR1 and hCAR2 and are each composed of at least 7 exons. Pseudogenes of this gene are found on chromosomes 15, 18, and 21.[3]

CAR is a transmembrane bound protein with two Ig-like extracellular domains, a transmembrane domain, a cytoplasmic domain, and two N-linked glycosylation sites. CAR contains two disulfide bonded loops (residues 35-130 and 155-220).[6] The N-terminal segment comprises the two extracellular domains (D1 and D2). D1 is most distal from the membrane and contains a V/Ig-like fold whereas D2 is more proximal. The cytoplasmic tail of CAR contains the amino acids G S I V, which is characterized as a class 1 PDZ-binding motif for interacting with proteins containing PDZ domains.[7]

The protein is found to be expressed in various regions of the body including the heart, brain, and, more generally, epithelial and endothelial cells. Moreover, CAR expression is not found in normal or tumor cell lines. Expression of CAR in endothelial cells can be regulated by treatment with drugs.[8] [9]

Function

It functions as a homophilic and heterophilic cell adhesion molecule through its interactions with extracellular matrix glycoproteins such as: fibronectin, agrin, laminin-1 and tenascin-R.[10] In addition, it is thought to regulate the cytoskeleton through interactions with actin and microtubules. Moreover, its cytoplasmic domain contains putative phosphorylation sites and a PDZ-interaction motif which suggests a scaffolding role.

Cardiac

CAR is essential for normal development of cardiomyocytes. The expression of CAR is high in developing tissues, including the heart and brain; postnatally it is expressed in epithelial cells and in adult cardiac muscle, it is localized at intercalated discs.[11] Knocking out CAR is embryonic lethal in mice by day 11.5, coordinate with severe cardiac muscle abnormalities including left ventricular hyperplasia, sinuatrial valve abnormalities, pericardial edema, thoracic hemorrhaging, myocardial wall degeneration, regional apoptosis, reduced density and disorganization of myofibrils, and enlarged mitochondria.[12] [13] [14] Cardiomyocyte-specific deletion of CAR after embryonic day 11 had no noticeable effect on development and postnatal life, suggesting that CAR is critical during a temporal window of cardiac development.[14]

It is clear from studies employing transgenesis that CAR function at intercalated discs in cardiac muscle is critical for normal heart function. Cardiac-specific knockout of CAR causes first degree block or complete block in the propagation of electrical conduction in the AV node. This was coordinate with the loss of connexin-45 at cell-cell junctions on the sarcolemmal membranes of AV node cells. Mice eventually developed cardiomyopathy associated with intercalated disc disorganization and loss of cardiomyocyte beta-catenin and ZO-1 expression; studies also showed that CAR, and connexin-45 form a protein complex that requires the PDZ-binding motif on CAR for proper formation. Moreover, CAR is required for normal localization of connexin-45, beta-catenin and ZO-1 at intercalated discs.[15]

Studies from human hearts have shown that lower expression of CXADR mRNA is associated with a risk allele at chromosome 21q21, which may in fact predispose hearts to arrhythmias. To discern the mechanistic underpinnings, hearts from heterozygous CAR knockout mice subjected to acute myocardial ischemia were evaluated and showed slowed ventricular conduction, earlier onset of ventricular arrhythmias, and increased susceptibility to arrhythmias. These findings were coordinate with a reduction in magnitude of the sodium current at intercalated discs; CAR coprecipitated with NaV1.5, which may provide a mechanistic link to this finding.[16]

Neural and lymphatic

CAR is strongly expressed in the developing central nervous system where it is thought to mediate neurite outgrowth. In addition, expression of CAR is readily detectable in the adult nervous system.[10]

It has also been shown that CAR is critical for the development of lymphatic vasculature and in forming lymphatic endothelial cell-cell junctions.[17]

Clinical significance

CAR is a receptor for both Coxsackie B virus and adenovirus 2 and 5, which are structurally distinct.[18]

In patients with myocarditis or dilated cardiomyopathy, elevated Coxsackie B2 viral nucleic acids have been detected in myocardial biopsy samples.[19] Adenoviral genomic DNA has also been detected in myocardial biopsies of patients with idiopathic cardiomyopathy, or impaired left ventricular function of unknown origin.[20] Patients exhibiting sudden death from acute myocardial infarction had a higher proportion of active coxsackie B virus infection relative to matched controls, which was coordinate with disrupted sarcolemmal localization of dystrophin, suggesting that enteroviral infection may worsen the outcome of patients with acute myocardial infarction.[21]

A role for CAR in arrhythmia susceptibility and ventricular fibrillation after myocardial infarction was shown in that CXADR lies near the 21q21 locus, which is strongly associated with these insults.[16] [22] [23] [24]

Interactions

CAR has been shown to interact with:MAGI-1b,[7] PICK1,[7] PSD-95,[7] ZO-1,[25] NaV1.5[16]

Further reading

Notes and References

  1. Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwitz MS, Crowell RL, Finberg RW . Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5 . Science . 275 . 5304 . 1320–3 . Feb 1997 . 9036860 . 10.1126/science.275.5304.1320 . 33824689 .
  2. Tomko RP, Xu R, Philipson L . HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses . Proceedings of the National Academy of Sciences of the United States of America . 94 . 7 . 3352–6 . Apr 1997 . 9096397 . 20373 . 10.1073/pnas.94.7.3352 . 1997PNAS...94.3352T . free .
  3. Web site: Entrez Gene: CXADR coxsackie virus and adenovirus receptor.
  4. Ifie. Eseoghene. Russell. Mark A.. Dhayal. Shalinee. Leete. Pia. Sebastiani. Guido. Nigi. Laura. Dotta. Francesco. Marjomäki. Varpu. Eizirik. Decio L.. Morgan. Noel G.. Richardson. Sarah J.. November 2018. Unexpected subcellular distribution of a specific isoform of the Coxsackie and adenovirus receptor, CAR-SIV, in human pancreatic beta cells. Diabetologia. 61. 11. 2344–2355. 10.1007/s00125-018-4704-1. 1432-0428. 6182664. 30074059.
  5. Web site: Protein sequence of human CXADR (Uniprot ID: P78310). Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 14 July 2015. https://web.archive.org/web/20150715024822/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P78310. 15 July 2015. dead.
  6. Tomko RP, Xu R, Philipson L . HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses . Proceedings of the National Academy of Sciences of the United States of America . 94 . 7 . 3352–6 . Apr 1997 . 9096397 . 10.1073/pnas.94.7.3352 . 20373. 1997PNAS...94.3352T . free .
  7. Excoffon KJ, Hruska-Hageman A, Klotz M, Traver GL, Zabner J . A role for the PDZ-binding domain of the coxsackie B virus and adenovirus receptor (CAR) in cell adhesion and growth . Journal of Cell Science . 117 . Pt 19 . 4401–9 . Sep 2004 . 15304526 . 10.1242/jcs.01300 . free .
  8. Funke C, Farr M, Werner B, Dittmann S, Uberla K, Piper C, Niehaus K, Horstkotte D . Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells . The Journal of General Virology . 91 . Pt 8 . 1959–70 . Aug 2010 . 20392896 . 10.1099/vir.0.020065-0 . free .
  9. Werner B, Dittmann S, Funke C, Überla K, Piper C, Niehaus K, Horstkotte D, Farr M . Effect of lovastatin on coxsackievirus B3 infection in human endothelial cells . Inflammation Research . 63 . 4 . 267–76 . Apr 2014 . 24316867 . 10.1007/s00011-013-0695-z . 18722233 .
  10. Patzke C, Max KE, Behlke J, Schreiber J, Schmidt H, Dorner AA, Kröger S, Henning M, Otto A, Heinemann U, Rathjen FG . The coxsackievirus-adenovirus receptor reveals complex homophilic and heterophilic interactions on neural cells . The Journal of Neuroscience . 30 . 8 . 2897–910 . Feb 2010 . 20181587 . 6633923. 10.1523/JNEUROSCI.5725-09.2010 .
  11. Kashimura T, Kodama M, Hotta Y, Hosoya J, Yoshida K, Ozawa T, Watanabe R, Okura Y, Kato K, Hanawa H, Kuwano R, Aizawa Y . Spatiotemporal changes of coxsackievirus and adenovirus receptor in rat hearts during postnatal development and in cultured cardiomyocytes of neonatal rat . Virchows Archiv . 444 . 3 . 283–92 . Mar 2004 . 14624362 . 10.1007/s00428-003-0925-9 . 768724 .
  12. Asher DR, Cerny AM, Weiler SR, Horner JW, Keeler ML, Neptune MA, Jones SN, Bronson RT, Depinho RA, Finberg RW . Coxsackievirus and adenovirus receptor is essential for cardiomyocyte development . Genesis . 42 . 2 . 77–85 . Jun 2005 . 15864812 . 10.1002/gene.20127 . 30511891 .
  13. Dorner AA, Wegmann F, Butz S, Wolburg-Buchholz K, Wolburg H, Mack A, Nasdala I, August B, Westermann J, Rathjen FG, Vestweber D . Coxsackievirus-adenovirus receptor (CAR) is essential for early embryonic cardiac development . Journal of Cell Science . 118 . Pt 15 . 3509–21 . Aug 2005 . 16079292 . 10.1242/jcs.02476 . free .
  14. Chen JW, Zhou B, Yu QC, Shin SJ, Jiao K, Schneider MD, Baldwin HS, Bergelson JM . Cardiomyocyte-specific deletion of the coxsackievirus and adenovirus receptor results in hyperplasia of the embryonic left ventricle and abnormalities of sinuatrial valves . Circulation Research . 98 . 7 . 923–30 . Apr 2006 . 16543498 . 10.1161/01.RES.0000218041.41932.e3 . free .
  15. Lim BK, Xiong D, Dorner A, Youn TJ, Yung A, Liu TI, Gu Y, Dalton ND, Wright AT, Evans SM, Chen J, Peterson KL, McCulloch AD, Yajima T, Knowlton KU . Coxsackievirus and adenovirus receptor (CAR) mediates atrioventricular-node function and connexin 45 localization in the murine heart . The Journal of Clinical Investigation . 118 . 8 . 2758–70 . Aug 2008 . 18636119 . 10.1172/JCI34777 . 2467382.
  16. Marsman RF, Bezzina CR, Freiberg F, Verkerk AO, Adriaens ME, Podliesna S, Chen C, Purfürst B, Spallek B, Koopmann TT, Baczko I, Dos Remedios CG, George AL, Bishopric NH, Lodder EM, de Bakker JM, Fischer R, Coronel R, Wilde AA, Gotthardt M, Remme CA . Coxsackie and adenovirus receptor is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia . Journal of the American College of Cardiology . 63 . 6 . 549–59 . Feb 2014 . 24291282 . 10.1016/j.jacc.2013.10.062 . 3926969.
  17. Mirza M, Pang MF, Zaini MA, Haiko P, Tammela T, Alitalo K, Philipson L, Fuxe J, Sollerbrant K . Essential role of the coxsackie- and adenovirus receptor (CAR) in development of the lymphatic system in mice . PLOS ONE . 7 . 5 . e37523 . 2012 . 22624044 . 10.1371/journal.pone.0037523 . 3356332. 2012PLoSO...737523M . free .
  18. Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwitz MS, Crowell RL, Finberg RW . Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5 . Science . 275 . 5304 . 1320–3 . Feb 1997 . 9036860 . 10.1126/science.275.5304.1320. 33824689 .
  19. Bowles NE, Richardson PJ, Olsen EG, Archard LC . Detection of Coxsackie-B-virus-specific RNA sequences in myocardial biopsy samples from patients with myocarditis and dilated cardiomyopathy . Lancet . 1 . 8490 . 1120–3 . May 1986 . 2871380 . 10.1016/s0140-6736(86)91837-4. 27035726 .
  20. Pauschinger M, Bowles NE, Fuentes-Garcia FJ, Pham V, Kühl U, Schwimmbeck PL, Schultheiss HP, Towbin JA . Detection of adenoviral genome in the myocardium of adult patients with idiopathic left ventricular dysfunction . Circulation . 99 . 10 . 1348–54 . Mar 1999 . 10077520 . 10.1161/01.cir.99.10.1348. free .
  21. Andréoletti L, Ventéo L, Douche-Aourik F, Canas F, Lorin de la Grandmaison G, Jacques J, Moret H, Jovenin N, Mosnier JF, Matta M, Duband S, Pluot M, Pozzetto B, Bourlet T . Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction . Journal of the American College of Cardiology . 50 . 23 . 2207–14 . Dec 2007 . 18061067 . 10.1016/j.jacc.2007.07.080 . free .
  22. Marsman RF, Wilde AA, Bezzina CR . Genetic predisposition for sudden cardiac death in myocardial ischaemia: the Arrhythmia Genetics in the NEtherlandS study . Netherlands Heart Journal . 19 . 2 . 96–100 . Feb 2011 . 21461030 . 10.1007/s12471-010-0070-4 . 3040308.
  23. Bezzina CR, Pazoki R, Bardai A, Marsman RF, de Jong JS, Blom MT, Scicluna BP, Jukema JW, Bindraban NR, Lichtner P, Pfeufer A, Bishopric NH, Roden DM, Meitinger T, Chugh SS, Myerburg RJ, Jouven X, Kääb S, Dekker LR, Tan HL, Tanck MW, Wilde AA . Genome-wide association study identifies a susceptibility locus at 21q21 for ventricular fibrillation in acute myocardial infarction . Nature Genetics . 42 . 8 . 688–91 . Aug 2010 . 20622880 . 10.1038/ng.623 . 3966292.
  24. Chopra N, Knollmann BC . Genetics of sudden cardiac death syndromes . Current Opinion in Cardiology . 26 . 3 . 196–203 . May 2011 . 21430528 . 10.1097/HCO.0b013e3283459893 . 3145336.
  25. Cohen CJ, Shieh JT, Pickles RJ, Okegawa T, Hsieh JT, Bergelson JM . The coxsackievirus and adenovirus receptor is a transmembrane component of the tight junction . Proceedings of the National Academy of Sciences of the United States of America . 98 . 26 . 15191–6 . Dec 2001 . 11734628 . 10.1073/pnas.261452898 . 65005. 2001PNAS...9815191C . free .

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