Relevance of signaling molecules for apoptosis induction on influenza A virus replication

Abstract

Apoptosis is an important mechanism to maintain homeostasis in mammals, and disruption of the apoptosis regulation mechanism triggers a range of diseases, such as cancer, autoimmune diseases, and developmental disorders. The severity of influenza A virus (IAV) infection is also closely related to dysfunction of apoptosis regulation. In the virus infected cells, the functions of various host cellular molecules involved in regulation of induction of apoptosis are modulated by IAV proteins to enable effective virus replication. The modulation of the intracellular signaling pathway inducing apoptosis by the IAV infection also affects extracellular mechanisms controlling apoptosis, and triggers abnormal host responses related to the disease severity of IAV infections. This review focuses on apoptosis related molecules involved in IAV replication and pathogenicity, the strategy of the virus propagation through the regulation of apoptosis is also discussed.

Keywords: Akt; Apaf-1; Apoptosis; B-cell lymphoma 2; BH; Bax; Bcl-2; Bcl-2 homology; Bcl-2-associated x protein; Caspases; DAP3; DR4; DR5; FADD; Fas-associated death domain; IAV; IFN; IFN regulatory factor 3; INF-β promoter stimulator protein 1; IPS-1; IRF3; Influenza A virus; JNK; M; NA; NF-κB; NP; NS1; PI3K; RIG-I; Signal transduction; TNF-related apoptosis inducing ligand; TNF-α; TNF-α receptor 1; TNFαR1; TRADD; TRAIL; X-linked inhibitor of apoptosis protein; XIAP; ZAPS; apoptotic protease activating factor 1; c-Jun amino-terminal kinase; cysteine–aspartic acid protease; death receptor 4; death receptor 5; death-associated protein 3; influenza A virus; interferon; matrix protein; neuraminidase; non-structural protein 1; nuclear factor-κB; nucleoprotein; phosphatidylinositol-3 kinase; retinoic acid-inducible gene-I; tumor necrosis factor receptor type 1-associated death domain protein; tumor necrosis factor α; v-akt murine thymoma viral oncogene homolog 1; zinc finger antiviral protein, short form.

Fig. 1

Two major pathways for induction of apoptosis and involvement of caspase-3 activation for IAV replication. Death receptor pathway and mitochondria pathway are crucial for the activation of caspase-8 and caspase-9 respectively. Disruption of mitochondrial membrane potential causes cytochrome c release, and activates caspase-9 by the complex formation with cytochrome c recognition protein, Apaf-1. After the activation of these pathways, both activated caspase-8 and caspase-9 activate caspase-3 by proteolytic cleavage.

Fig. 2

Modulation of IAV replication by death receptor-mediated signaling pathway. In addition to caspase 8 activation, death receptors activate NF-κB and JNK signaling pathways. IAV NS1 and NA are involved in activation of NF-κB through the activation of Akt, and NS1 also has a function to inhibit the JNK activation.

Fig. 3

IPS-1-mediated apoptosis induction pathway activated by IAV infection. IPS-1 is responsible to activate a transcriptional factor, IRF3. IRF3 induces the transcription of pro-apoptotic proteins, Noxa and Puma. IPS-1-mediated phosphorylation of IRF3 leads binding of IRF3 to Bax, and promotes Bax-induced apoptosis. Functions of IPS-1 are inhibited by IAV proteins, NS1, blocking the function of RIG-I, and the viral polymerase complex.

Fig. 4

Other apoptosis induction factors involved in IAV replication. Siva-1 is involved in the effective IAV replication through the activation of caspases. DAP3 is essential for death receptor-mediated apoptosis induction and IPS-1-induced anoikis, suggesting that DAP3 is an important molecule to regulate apoptosis induced by IAV infection.