Coordination of Zika Virus Infection and Viroplasm Organization by Microtubules and Microtubule-Organizing Centers

Abstract

Zika virus (ZIKV) became a global health concern in 2016 due to its links to congenital microcephaly and other birth defects. Flaviviruses, including ZIKV, reorganize the endoplasmic reticulum (ER) to form a viroplasm, a compartment where virus particles are assembled. Microtubules (MTs) and microtubule-organizing centers (MTOCs) coordinate structural and trafficking functions in the cell, and MTs also support replication of flaviviruses. Here we investigated the roles of MTs and the cell’s MTOCs on ZIKV viroplasm organization and virus production. We show that a toroidal-shaped viroplasm forms upon ZIKV infection, and MTs are organized at the viroplasm core and surrounding the viroplasm. We show that MTs are necessary for viroplasm organization and impact infectious virus production. In addition, the centrosome and the Golgi MTOC are closely associated with the viroplasm, and the centrosome coordinates the organization of the ZIKV viroplasm toroidal structure. Surprisingly, viroplasm formation and virus production are not significantly impaired when infected cells have no centrosomes and impaired Golgi MTOC, and we show that MTs are anchored to the viroplasm surface in these cells. We propose that the viroplasm is a site of MT organization, and the MTs organized at the viroplasm are sufficient for efficient virus production.

Integrated protein-protein interaction and RNA interference screens reveal novel restriction and dependency factors for a tick-borne flavivirus in its human host

“…NS5 of Dengue and ZIKA viruses (DENV and ZIKV) are known to localize at centrosomes during cell division 45,46 . While formation of the ZIKV viroplasm is closely associated with the centrosome and the Golgi MTOC 47 , neither viroplasm formation nor virus production are significantly impaired in the absence of centrosomes. Thus, the functional significance of interactions between flavivirus proteins with centrosomes remains ill-defined.…”

Isobaric tags for relative and absolute quantification-based proteomic analysis of host-pathogen protein interactions in the midgut of Aedes albopictus during dengue virus infection

“…Among them, A0A023ETG9 belongs to microtubule (MT) protein, the development of the nervous system is highly dependent on the microtubule cytoskeleton, and mutations in microtubule protein can cause a series of neurological diseases ( Tischfield et al, 2010 ). According to reports, depolymerization or stabilization of MTs can affect virus transport to the endoplasmic reticulum and virus production, and when MTs are disrupted, the number of released virus particles is significantly reduced ( Buchwalter et al, 2021 ; Qi et al, 2022 ), the expression of A0A023ETG9 decreased in the virus-infected group, which indicates that MT is associated with DENV infection, and this could be a target to inhibit virus replication, but its principle and mechanism need to be further investigated.…”

Congenital Zika syndrome

“…In these vesicles, the structural proteins are integrated, a process necessary for their transport into the cell, mainly through the interaction of the E protein and prM with the Golgi apparatus 28,31,32 . At the same time, ZIKV generates modifications in centrosomes to reorganize microtubules and facilitate their transport and intracellular propagation 33,34 . Subsequently, for viral release into the extracellular environment, it was described that ZIKV can induce a process of apoptosis mediated by autophagy, processes of degranulation of viral RNA packaging vesicles, or processes of exocytosis 34 .…”

“…At the same time, ZIKV generates modifications in centrosomes to reorganize microtubules and facilitate their transport and intracellular propagation 33,34 . Subsequently, for viral release into the extracellular environment, it was described that ZIKV can induce a process of apoptosis mediated by autophagy, processes of degranulation of viral RNA packaging vesicles, or processes of exocytosis 34 . The NS5 viral protein antagonizes the type I interferon response to favor viral dissemination.…”