Regulation of Apoptosis by Enteroviruses

Abstract

Enterovirus infection can cause a variety of diseases and severely impair the health of humans, animals, poultry, and other organisms. To resist viral infection, host organisms clear infected cells and viruses via apoptosis. However, throughout their long-term competition with host cells, enteroviruses have evolved a series of mechanisms to regulate the balance of apoptosis in order to replicate and proliferate. In the early stage of infection, enteroviruses mainly inhibit apoptosis by regulating the PI3K/Akt pathway and the autophagy pathway and by impairing cell sensors, thereby delaying viral replication. In the late stage of infection, enteroviruses mainly regulate apoptotic pathways and the host translation process via various viral proteins, ultimately inducing apoptosis. This paper discusses the means by which these two phenomena are balanced in enteroviruses to produce virus-favoring conditions - in a temporal sequence or through competition with each other. This information is important for further elucidation of the relevant mechanisms of acute infection by enteroviruses and other members of the picornavirus family.

Keywords: apoptotic pathway; balance; enterovirus; regulation; viral replication.

FIGURE 1

Link between pathogen recognition and apoptosis. (1) The death ligands TNF and FasL bind to their corresponding receptors, TNFR and Fas, and recruit TRADD and FADD, respectively, which then bind to procaspase 8 to form the death-inducing signaling complex (DISC) to activate caspase 8. (2) RIG-1 or MDA-5 recognizes viral dsRNA and recruits IPS-1. Activated IPS-1 recruits FADD and RIPK1 to form a complex and then recruits and activates procaspase 8. (3) TLR-3 recognizes viral dsRNA in the cytoplasm and exposes the TIR domain. The adaptor TRIF containing the TIR domain binds to RIPK. The C-terminus of RIPK1 has a death domain (DD), which can interact with FADD, after which FADD recruits and activates procaspase 8. (a) Activated IPS-1 can also recruit IKKε and TBK1, causing phosphorylation and dimerization of IRF-3. The IRF-3 homodimer can translocate to the mitochondrial membrane and form a complex with Bax. (b) Activated caspase 8 can cleave Bid to form tBid with proapoptotic activity, which can induce Bax and Bak to insert into the outer mitochondrial membrane. (c) Bax or Bak undergoes conformational changes and forms heterodimers or homodimers, thereby destroying the mitochondrial membrane and reducing the mitochondrial membrane potential. Subsequently, mitochondria release Cyt c into the cytoplasm. (d,e) Cyt c, procaspase 9 and Apaf-1 combine to form a complex that cleaves procaspase 9 into caspase 9. (A) Caspase 9 and caspase 8 cleave procaspase 3 into caspase 3. (B) Caspase 3 translocates to the nucleus and activates proteins, ultimately leading to apoptosis. The image content has been borrowed from other articles in the literature (Croft et al., 2017; Sun et al., 2019).

FIGURE 2

Enteroviruses regulate apoptosis through the PI3K/AKT pathway. (a) Enteroviruses interact with cellular receptors to induce JNK phosphorylation. (b) Activated JNK activates Bax-dependent apoptosis. (1) Enteroviruses interact with cell receptors to activate the PI3K/AKT pathway. (2) PI3K activates Akt by phosphorylating threonine (Thr) 308 and serine (Ser) 473 on Akt. (3) Activated Akt phosphorylates NF-κB, MDM2, and ASK1. Phosphorylation of NF-κB activates its transcription function, allowing it to enhance the expression of the antiapoptotic protein Bcl-xl. Phosphorylated MDM2 can inactivate or degrade P53, thereby blocking the P53-mediated proapoptotic transcription reaction. (4) Activated Akt directly phosphorylates Bad, Bax, and caspase 9, causing them to lose their ability to promote apoptosis and thereby effectively blocking apoptosis. (5) ASK1 is the upstream regulatory factor of JNK, and phosphorylated ASK1 negatively regulates the activation of JNK, thereby delaying activation of the proapoptotic protein Bax and effectively inhibiting apoptosis.

FIGURE 3

Enteroviruses regulate miRNAs to induce apoptosis. Apoptosis induced by enterovirus infection is associated with the regulation of microRNAs (miRNAs) (Chang et al., 2015; Jiang et al., 2019). The red dotted line indicates the site of enteroviral action, and the red solid arrows indicate the up- or downregulation of the expression of each protein.

FIGURE 4

Relationship between autophagy and apoptosis induced by CVB3. (1) After CVB3 infects cells, it uses viral proteins (such as 2BC and 3A) to induce autophagy. (2) The direct actions of viral proteins (such as 3C and 2A) or the cell’s defense mechanisms then activate caspases and calpain through various pathways. (3) The transcription and translation of full-length ATG5 and beclin-1 in CVB3-infected cells continue to increase. (4) Beclin-1 aids in autophagosome initiation and autophagosome blockade, Atg5 aids in autophagosome extension, and Beclin-1 can stimulate high levels of autophagy. (5) Endoplasmic reticulum-localized Bcl-2 can form a complex with Beclin-1. (6) Upon forming a complex with Bcl-2, Beclin-1 loses its ability to induce autophagy. (7) Beclin-1 is cleaved by caspases, while Atg5 can be cleaved by calpains. (8) The C-terminal cleavage product of Beclin-1 is transferred to mitochondria and induces Cyt c release; the N-terminal cleavage product of Atg5 is also transferred to mitochondria and induces Cyt c release after binding to Bcl-xL. The release of cyt c into the cytoplasm leads to apoptosis. (9) Caspase-mediated destruction of the Beclin-1-Bcl-2 complex promotes autophagy. The image content has been adapted from other articles in the literature (Gordy and He, 2012; Jiang et al., 2014).

FIGURE 5

Mechanism by which enteroviruses balance apoptosis. Enteroviruses inhibit apoptosis in the early stages of infection to prolong their replication time but induce apoptosis in the late stage of infection to facilitate the release of progeny virus.