The PDZ1 and PDZ3 domains of MAGI-1 regulate the eight-exon isoform of the coxsackievirus and adenovirus receptor.
Epithelial integrity is essential for homeostasis and poses a formidable barrier to pathogen entry. Major factors for viral entry into epithelial cells are the localization and abundance of the primary receptor. The coxsackievirus and adenovirus receptor (CAR) is a primary receptor for these two pathogenic groups of viruses. In polarized epithelia, a low-abundance, alternatively spliced eight-exon isoform of CAR, CAR(Ex8), is localized apically where it can support viral infection from the air-exposed surface. Using biochemical, cell biology, genetic, and spectroscopic approaches, we show that the levels of apical CAR(Ex8) are negatively regulated by the PDZ domain-containing protein MAGI-1 (membrane-associated guanylate kinase with inverted orientation protein-1) and that two MAGI-1 PDZ domains, PDZ1 and PDZ3, regulate CAR(Ex8) levels in opposing ways. Similar to full-length MAGI-1, expression of the isolated PDZ3 domain significantly reduces cell surface CAR(Ex8) abundance and adenovirus infection. In contrast, the PDZ1 domain is able to rescue CAR(Ex8) and adenovirus infection from MAGI-1-mediated suppression. These data suggest a novel cell-based strategy to either suppress viral infection or augment adenovirus-based gene therapy.
Department of Biological Sciences, Wright State University, Dayton, Ohio, USA.
Abimbola Olayinka
AO
Kolawole
Priyanka
P
Sharma
Ran
R
Yan
Kyle Joseph Edward
KJ
Lewis
Zhigang
Z
Xu
Heather Ann
HA
Hostetler
Katherine Julie Diane
KJ
Ashbourne Excoffon
D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000502:physiology; D000257:Adenoviridae Infections / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D017398:Alternative Splicing; D000818:Animals; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003384:Coxsackievirus Infections / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D015536:Down-Regulation; D004770:Enterovirus / Q000502:physiology; D005091:Exons; D051528:Guanylate Kinases; D006801:Humans; D054731:PDZ Domains; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000235:genetics* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C568771:CLMP protein, human; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus; D051528:Guanylate Kinases; C113338:MAGI1 protein, human