HEV replication is promoted by blocking the NF-κB signaling pathway through inhibiting FLNa expression

ABSTRACT Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide. Filamin A (FLNa), a cytoskeletal protein, is involved in cytoskeleton remodeling to construct a barrier to infection and participates in virus entry and release. However, how HEV enters host cells and how it is sensed by pattern recognition receptors are largely unexplored. In this study, the role of FLNa during HEV infection was evaluated in patients with HEV infection, animal models, and cell cultures. Notably, HEV interacted with FLNa at the early stage of infection and remarkably inhibited the expression of FLNa in vivo and in vitro . Its knockdown inhibited the proteolytic degradation of IκB, thus blocking the nuclear translocation of NF-κB. As a result, robust viral replication occurred, and numerous virions were released. Furthermore, the inhibition of FLNa suppressed ubiquitination-mediated degradation to aggravate apoptosis and inflammatory responses. Results indicated that FLNa plays a critical role in the remodeling of the cytoskeletal network during HEV infection. This role may be responsible for the easy entry and escape of HEV from sensing by innate immunity. IMPORTANCE Hepatitis E virus (HEV) is the most common pathogen of acute viral hepatitis. The mechanisms by which HEV enters host cells and is sensed by pattern recognition receptors are largely unexplored. In the present study, filamin A (FLNa), a cytoskeletal protein, was significantly inhibited in patients with HEV infection, animal models, and cell cultures. The knockdown of FLNa facilitates viral replication by blocking the nuclear translocation of NF-κB while inhibiting ubiquitination-mediated degradation to aggravate apoptosis and inflammatory responses. This work demonstrates that FLNa plays a critical role in the remodeling of the cytoskeletal network during HEV infection. Such remodeling may be responsible for the entry and escape of HEV from sensing by innate immunity.