Advisory Committee Chair
William Britt
Advisory Committee Members
Jim Collawn
Terje Dokland
Janusz Kabarowski
Elizabeth Sztul
Document Type
Dissertation
Date of Award
2008
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
HCMV consists of a dsDNA genome enclosed by, an icosahedral capsid surrounded by a layer of tegument proteins; the virion structure is enclosed in a lipid envelope rich in virus expressed glycoproteins. The HCMV envelope contains an incompletely defined number of glycoproteins. The glycoprotein M (gM) and glycoprotein N (gN) form a gM/gN protein complex which is the most abundant protein component of the HCMV envelope. Recent studies have indicated that deletion of the viral gene encoding either gM or gN is lethal for HCMV. The gM C-terminal cytoplasmic tail (gM-CT) revealed an acidic cluster and a tyrosine-based trafficking motifs. Mutant viruses that lacked the entire cytoplasmic tail of gM or both trafficking motifs were not viable. These results suggested that the trafficking motifs in the gM-CT are indispensable for virus replication. Mutant viruses with acidic cluster deletion or alanine substitutions in the tyrosine-based motif were viable but exhibited a delayed growth phenotype resulting in reduced infectious virus production. These results suggested that gM-CT possibly interacts with cellular proteins that regulate the rate of gM/gN intracellular trafficking. We found that the gM-CT interacts with FIP4 effector of the Rab11. Depletion of FIP4 expression or inhibition of Rab11 function during HCMV infection resulted in lower infectious virus production. It has been previously shown that simultaneous interactions of FIP4 with Arf6/Arf5 and Rab11 were important for vesicular transport of proteins into the endosomal recycling ii compartment (ERC). Surprisingly, FIP4 interactions with gM-CT inhibited binding of FIP4 to Arf5 or Arf6. These data argued for a contribution of the ERC during HCMV final envelopment and revealed a novel function of Rab11 independent of Arf5 or Arf6 activity. Our results suggested a role for the glycoprotein gM during virus assembly, particularly with respect to the dynamics of gM/gN complex trafficking during viral particle assembly. We also demonstrated the involvement of the cellular Rab11 GTPase activity, which is critical during the final maturation of HCMV particles.
Recommended Citation
Krzyzaniak, Magdalena Anna, "Role Of The Gm/Gn Glycoprotein Complex In The Final Assembly And Egress Of The Human Cytomegalovirus (Hcmv)" (2008). All ETDs from UAB. 3738.
https://digitalcommons.library.uab.edu/etd-collection/3738