Abstract
Cytomegalovirus (CMV) infection initiates massive rearrangement of cytoplasmic organelles to generate assembly compartment (AC). The earliest events, the establishment of the preAC, are initiated in the early phase as an extensive reorganization of early endosomes (EEs), endosomal recycling compartment (ERC), trans-Golgi network (TGN), and the Golgi. Here, we demonstrate that dynamin inhibitors (Dynasore, Dyngo-4a, MiTMAB, and Dynole-34-2) block the establishment of the preAC in murine CMV (MCMV) infected cells. In this study, we extensively analyzed the effect of Dynasore on the Golgi reorganization sequence into the outer preAC. We also monitored the development of the inner preAC using a set of markers that define EEs (Rab5, Vps34, EEA1, and Hrs), the EE-ERC interface (Rab10), the ERC (Rab11, Arf6), three layers of the Golgi (GRASP65, GM130, Golgin97), and late endosomes (Lamp1). Dynasore inhibited the pericentriolar accumulation of all markers that display EE-ERC-TGN interface in the inner preAC and prevented Golgi unlinking and dislocation to the outer preAC. Furthermore, in pulse-chase experiments, we demonstrated that the presence of dynasore only during the early phase of MCMV infection (4–14 hpi) is sufficient to prevent not only AC formation but also the synthesis of late-phase proteins and virion production. Therefore, our results indicate that dynamin-2 acts as a part of the machinery required for AC generation and rearrangement of EE/ERC/Golgi membranes in the early phase of CMV infection.
Highlights
Cytomegaloviruses (CMV) are large DNA viruses that belong to a family of βherpesviruses and cause life-long asymptomatic infections in around 70% of the population.after congenital infections and infections in immunocompromised patients, the virus severely damages the infected organism, often with the fatal outcome
We have previously shown that reorganization of host-cell compartments is initiated in the early phase of murine CMV (MCMV) infection and results in the development of preAC [10]
This primordial structure develops into mature assembly compartment (AC), characterized by pericentriolar accumulation of EE, endosomal recycling compartment (ERC), and trans-Golgi network (TGN)-derived membranous structures in the inner area surrounded by reorganized Golgi stacks into the outer ring-like formation
Summary
Cytomegaloviruses (CMV) are large DNA viruses that belong to a family of βherpesviruses and cause life-long asymptomatic infections in around 70% of the population.after congenital infections and infections in immunocompromised patients, the virus severely damages the infected organism, often with the fatal outcome. It is well established that massive reorganization of membranous organelles is essential for developing the sites required for final envelopment and egress of nascent virions. These rearrangements include early endosomes (EE), endosomal recycling compartment (ERC), the trans-Golgi network (TGN), and the Golgi system, both in HCMV [6,7,8] and MCMV [9,10] infected cells. The reorganized membranous organelle structure in the early phase of infection, before viral DNA replication and expression of viral structural proteins is considered the preAC [10,13]
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