Coxsackievirus entry across epithelial tight junctions requires occludin and the small GTPases Rab34 and Rab5.
The major group B coxsackievirus (CVB) receptor is a component of the epithelial tight junction (TJ), a protein complex that regulates the selective passage of ions and molecules across the epithelium. CVB enters polarized epithelial cells from the TJ, causing a transient disruption of TJ integrity. Here we show that CVB does not induce major reorganization of the TJ, but stimulates the specific internalization of occludin-a TJ integral membrane component-within macropinosomes. Although occludin does not interact directly with virus, depletion of occludin prevents CVB entry into the cytoplasm and inhibits infection. Both occludin internalization and CVB entry require caveolin but not dynamin; both are blocked by inhibitors of macropinocytosis and require the activity of Rab34, Ras, and Rab5, GTPases known to regulate macropinocytosis. Thus, CVB entry depends on occludin and occurs by a process that combines aspects of caveolar endocytosis with features characteristic of macropinocytosis.
Coyne
Carolyn B
CB
Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. coynec2@pitt.edu
Shen
Le
L
Turner
Jerrold R
JR
Bergelson
Jeffrey M
JM
D022461:Caveolins / Q000502:physiology; D002460:Cell Line; D034281:Dynamins / Q000502:physiology; D004705:Endocytosis / Q000502:physiology; D029822:Enterovirus B, Human / Q000502:physiology*; D004847:Epithelial Cells / Q000821:virology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D062793:Occludin; D019108:Tight Junctions / Q000821:virology*; D053586:Virus Internalization; D020691:rab GTP-Binding Proteins / Q000502:physiology*; D020696:rab5 GTP-Binding Proteins / Q000502:physiology*; D020703:ras GTPase-Activating Proteins / Q000502:physiology
D022461:Caveolins; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D020703:ras GTPase-Activating Proteins; C474116:RAB39A protein, human; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins; D034281:Dynamins