The proapoptotic influenza A virus protein PB1-F2 regulates viral polymerase activity by interaction with the PB1 protein

Abstract

SummaryThe 11 th influenza A virus protein PB1-F2 was previously shown to enhance apoptosis in response to cytotoxic stimuli. The 87 amino acid protein that is encoded by an alternative reading frame of the PB1 polymerase gene was described to localize to mitochondria consistent with its proapoptotic function. However, PB1-F2 is also found diffusely distributed in the cytoplasm and in the nucleus suggesting additional functions of the protein. Here we show that PB1-F2 colocalizes and directly interacts with the viral PB1 polymerase protein. Lack of PB1-F2 during infection resulted in an altered localization of PB1 and decreased viral polymerase activity. Consequently, mutant viruses devoid of a functional PB1-F2 reading frame exhibited a small plaque phenotype. Thus, we have identified a novel function of PB1-F2 as an indirect regulator of the influenza virus polymerase activity via its interaction with PB1.

Influenza A Virus Infections in Swine

“…72,130,151 Within host cells, the protein associates most extensively with mitochondria but has also been detected in both cytoplasm and nucleus. 18,94 The results of multiple in vitro and in vivo studies in various cell lines and experimental animals suggest the protein contributes to virulence through several functions: (1) apoptosis induction, primarily in cells of the innate immune system; (2) suppression of early interferon response by infected cells; (3) increased viral replication rates or delayed viral clearance; and (4) increased inflammation in host tissues. Nearly all of these functions require cooperative interaction of the PB1-F2 with other cellular or virus-induced proteins.…”

“…Co-localization of the protein with PB1 in the nucleus leads to increased polymerase activity and likely consequent increased viral replication. 94 In a mouse model, insertion of PB1-F2 from the 1918 H1N1 pandemic virus into a laboratory-adapted virus resulted in a higher viral production rate per cell and a higher infected cell rate. 130 Contrarily, in another mouse model study, virus replication rates were not increased, but virus clearance was delayed.…”

“…Viruses may enhance their infectivity by inhibiting caspase activity until sufficient replication of viral proteins has been completed. 46,79,94,168 Contrarily, in a case of Highly Pathogenic Avian Influenza (HPAI) zoonosis, an H5N1 virus isolated from a human fatality induced more cellular apoptosis in vitro than less virulent viruses of other subtypes. 75 …”

Evolution of highly pathogenic avian H5N1 influenza viruses and the emergence of dominant variants

“…PB1-F2 functions as a pro-apoptotic factor (Chen et al, 2001;Zamarin et al, 2005), enhances inflammation in mice and increases the severity of secondary bacterial infections (McAuley et al, 2007). Moreover, it interacts with the PB1 protein to retain it in the nucleus and may, through this mechanism, affect virulence (Mazur et al, 2008). Currently, it is not clear if the C-terminal truncation of NS1 and the truncation of PB1-F2 are functionally linked.…”

Molecular studies of influenza B virus in the reverse genetics era

“…The roles of PB1-F2 and N40 for influenza A viruses are still not completely clear. Although neither protein is absolutely required for replication, PB1-F2 may enhance virulence of influenza A viruses by either enhancing replication (Mazur et al, 2008) or affecting immune functions predisposing hosts to secondary bacterial infections (McAuley et al, 2007). At present the influenza B virus genome appears devoid of PB1-F2 or N40 orthologues.…”