Zika Virus Hijacks ANKLE2 Protein to Promote Viral Replication and Cause Microcephaly

The Zika virus (ZIKV), a mosquito-borne pathogen, has long been associated with severe birth defects, particularly microcephaly—a condition where infants are born with abnormally small heads and underdeveloped brains. Recent scientific breakthroughs have revealed how the virus manipulates a key human protein, ANKLE2, which is vital for brain progress, to fuel its own replication.This discovery provides critical insights into Zika’s unique ability to disrupt fetal development and cause lasting harm.

Published in the journal mBio, the study titled “Microcephaly protein ANKLE2 promotes Zika virus replication” highlights the virus’s reliance on ANKLE2 for replication.Researchers found that Zika and related viruses exploit this protein, which is essential for tissue development, especially in the brain. As the authors stated, “ZIKV and other orthoflaviviruses hijack ANKLE2 for a conserved role in replication, and this drives unique pathogenesis for ZIKV since ANKLE2 has essential roles in developing tissues.”

Orthoflaviviruses, a family of single-stranded RNA viruses, are responsible for some of the most devastating diseases worldwide. “Many orthoflaviviruses, such as Zika virus (ZIKV), dengue virus (DENV), West Nile virus (WNV), and yellow fever virus (YFV), are transmitted by mosquitoes and represent important public health threats globally,” the researchers explained. Thes viruses, despite their limited genetic material, are adept at hijacking host proteins to replicate, a process that has been the focus of extensive study.

Zika virus first captured global attention during a 2015 outbreak that spread rapidly across South and Central America. While adults infected with Zika often experience mild symptoms, the virus poses a grave threat to unborn children, causing congenital Zika syndrome (CZS). “CZS is a spectrum of disease and can be clinically characterized by multiple hallmark features, including congenital contractures, ocular anomalies, cortical calcifications, and in the most severe cases, microcephaly,” the team emphasized. Microcephaly, in particular, is linked to developmental delays, intellectual disabilities, and an increased risk of seizures.

Previous research by the team uncovered a crucial interaction between a Zika virus protein, NS4A, and the host protein ANKLE2. “By searching for host proteins with known roles in neurodevelopment or associations with microcephaly, we identified the interaction between ZIKV NS4A and host ankyrin repeat and LEM domain-containing 2 (ANKLE2),” they wrote. Using fruit flies as a model, they demonstrated that this interaction could induce microcephaly. “Using this Drosophila model, we previously showed that transgenic expression of ZIKV NS4A induces similar microcephaly phenotypes which are also rescued by the expression of human ANKLE2.”

ANKLE2, a protein critical for fetal brain development, is present in cells throughout the body. In their latest study, led by recent PhD graduate Adam Fishburn, the team grew Zika virus in human cells and found that disabling the ANKLE2 gene significantly impaired the virus’s ability to replicate. This finding highlights the protein’s indispensable role in viral proliferation.

Shah elaborated on the process,explaining that the viral NS4A protein interacts with ANKLE2 to create specialized structures off the endoplasmic reticulum,effectively forming virus production hubs. “Bringing all the components to make viruses in one place makes replication more efficient and also helps hide the virus from the immune system,” he noted.

. In⁤ zika-infected cells, ANKLE2 clusters around the endoplasmic reticulum, a network responsible for protein production within the cell. ⁢”Microscopy ‌suggested that‍ ANKLE2 KO results in fewer⁣ and poorly formed virus replication organelles and significantly altered membrane rearrangements,” the team wrote.​ shah added, “Our current model is that‌ ANKLE2 ⁤is ‍really crucial, but ‌not essential, for forming these replication pockets.”

Collaborating with Claudia Rückert,PhD,at‌ the University of Nevada,the researchers found that Zika virus⁤ also utilizes ANKLE2 in mosquito cells,indicating that this interaction is vital across both human and insect hosts.​ “Moreover, we show that ‌silencing of‌ the ANKLE2 ortholog in ⁣mosquito cells also reduces ZIKV replication, suggesting a conserved role in replication across hosts,” they observed.

One intriguing question arises: why⁢ doesn’t dengue virus, which also targets ANKLE2, cause microcephaly like Zika? The answer lies in location.Zika virus uniquely crosses the placenta, entering the fetus where ANKLE2 is heavily involved in brain development.Most other viruses are blocked by the placental barrier.”Thus, ZIKV’s unique pathogenesis derived from the NS4A-ANKLE2 interactions is from being ⁣in the wrong place at the wrong time when it comes ⁢to ANKLE2,” the scientists concluded.