Abstract
Influenza remains a serious worldwide public health problem. After infection, viral genomic RNA is replicated in the nucleus and packed into viral ribonucleoprotein, which will then be exported to the cytoplasm via a cellular chromosome region maintenance 1 (CRM1)-dependent pathway for further assembly and budding. However, the nuclear export mechanism of influenza virus remains controversial. Here, we identify cellular nuclear transport factor 2 (NTF2)-like export protein 1 (NXT1) as a novel binding partner of nucleoprotein (NP) that stimulates NP-mediated nuclear export via the CRM1-dependent pathway. NXT1-knockdown cells exhibit decreased viral replication kinetics and nuclear accumulated viral RNA and NP. By contrast, NXT1 overexpression promotes nuclear export of NP in a CRM1-dependent manner. Pull-down assays suggest the formation of an NXT1, NP, and CRM1 complex, and demonstrate that NXT1 binds to the C-terminal region of NP. These findings reveal a distinct mechanism for nuclear export of the influenza virus and identify the NXT1/NP interaction as a potential target for antiviral drug development.
Highlights
Influenza virus infection has resulted in several serious pandemics e.g., Spanish influenza (H1N1)in 1918 [1] and the swine influenza (H1N1) in 2009 [2]
Later studies showed that NXT1 is a critical cofactor for transporter associated with antigen processing (TAP)-mediated mRNA nuclear export by formation of a TAP/NXT1 heterodimer that enhances the TAP/RNA interaction with nucleoporins at the nuclear pore complex (NPC) [35,36,37]
A role for NXT1 in chromosome region maintenance 1 (CRM1)-dependent nuclear export was demonstrated in digitonin-permeabilized cells by the addition of NXT1, which stimulated the nuclear export of nuclear export signals (NESs)-containing protein protein kinase inhibitor (PKI)
Summary
Influenza virus infection has resulted in several serious pandemics e.g., Spanish influenza (H1N1)in 1918 [1] and the swine influenza (H1N1) in 2009 [2]. Human infections with a new avian influenza A (H7N9) subtype were reported in China in 2013 [3]. Few antiviral drugs have been approved by the U.S Food and Drug Administration, including oseltamivir, zanamivir, and peramivir, all of which target viral neuraminidase (NA) to inhibit viral release from host cells, and the development and transmission of oseltamivir- or zanamivir-resistant viruses has been reported [4,5,6,7]. Targeting at the unconventional nuclear localization signal (NLS) of NP by mycalamide analogs results in a reduction of viral replication [11]. Inhibition of NP nuclear localization by nucleozin and its analogs potentially decreases in vitro and in vivo viral replication [12,13]. Our previous comparative study of influenza nuclear export signals (NESs), including matrix 1 (M1)-NES, non-structural 1
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