New Research Highlights Role of Key Protein in HCV

Scientists now have a clearer understanding of how the protein NS5A gets around the body’s cellular defenses.

A new study has given researchers an increased understanding of a how a key hepatitis C virus (HCV) protein subverts the body’s defenses.

The research, conducted by teams in Italy and the United Kingdom, more clearly elucidates the interaction between the viral nonstructural protein NS5A and the nucleosome assembly protein 1-like 1 (NAP1L1).

Alessandro Marcello (pictured), PhD, head of the laboratory for molecular virology at the International Centre for Genetic Engineering and Biotechnology, in Trieste, Italy, said the NS5A is something of a Swiss army knife, in that it performs a number of functions related to the replication of HCV and the virus’ interaction with the host’s cells.

Several previous screens have suggested an interaction between NS5A and NAP1L1. Marcello told MD Magazine that he and his colleagues wanted to see why NS5A might be targeting NAP1L1.

“The nucleosome assembly protein NAP1L1 came up consistently as interactor of NS5A and this was quite intriguing for us because in the past we identified the same protein as a target of HIV,” Marcello said. “It is not unusual that different viruses target a critical cellular factor to promote their own growth, so we speculated that NAP1L1 could have an unexpected and general role in protecting cells from infection.”

Marcello and colleagues confirmed that role and located the interaction at the C terminus of NS5A in both genotypes 1 and 2 of HCV. They found that NS5A from genotype 2 (but not genotype 1) targets NAP1L1 for proteosome-mediated degradation.

Finally, the researchers gained a better understanding of the importance NAP1L1 plays in helping the cell protect itself from the HCV virus.

“Among those, we showed that lack of NAP1L1 leads to a decrease of RELA protein levels and a strong defect of IRF3 TBK1/IKKε-mediated phosphorylation, leading to inefficient RIG-I and Toll-like receptor 3 (TLR3) responses,” the researchers wrote.

Thus, NAP1L1 can be a fruitful target for NS5A and HCV.

Going forward, Marcello said additional research is needed to more fully understand the role and function of NAP1L1.

Marcello noted that their research indicated that NS5A is only effective for certain types of HCV genotypes (1 and 2). It is already known that patient response to interferon therapy can vary depending on HCV genotype (patients with genotypes 2 and 3 tend to show a better response).

“Therefore, genetic variability of NS5A could impact the response to interferon therapy, which is still is the only therapeutic option in several underdeveloped places in the world that cannot afford antiviral drugs,” Marcello said.

Marcello said a better understanding of how exactly NAP1L1 functions could create an interesting pathway to potential autoimmune therapies.

"Intriguingly, this factor is cytoplasmic at steady-state and travels to the nucleus only under specific circumstances,” Marcello said. “Cellular factors may control NAP1L1 activity similarly to viral NS5A by blocking nuclear translocation and releasing NAP1L1 to the nucleus only in response to stimuli.

Since researchers found that down-modulating NAP1L1 reduces the innate cellular response, it could become an interesting therapeutic target for "autoimmune diseases that are characterized by a hyper-activated innate response," Marcello said.

The study, "Hepatitis C Virus NS5A Targets Nucleosome Assembly Protein NAP1L1 To Control the Innate Cellular Response," was published online in the Journal of Virology this month.

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