The Interplays between Autophagy and Apoptosis Induced by Enterovirus 71

Xi, Xueyan; Zhang, Xiaoyan; Wang, Bei; Wang, Tao; Wang, Ji; Huang, He; Wang, Jianwei; Jin, Qi; Zhao, Zhendong

doi:10.1371/journal.pone.0056966

Cited by 61 publications

(60 citation statements)

References 44 publications

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“…Wang et al showed that the virulence of coxsackie virus B3 was markedly inhibited when apoptosis was inhibited (44). Xi et al also demonstrated that the inhibition of apoptosis prevents EV71 viral particle release (45), and our data also confirmed this finding. In this study, we found that EV71 3C induced apoptosis through cleaving PinX1 and that knockdown of PinX1 promotes apoptosis, which facilitates EV71 release.…”

Section: Discussionsupporting

confidence: 90%

Enterovirus 71 3C Promotes Apoptosis through Cleavage of PinX1, a Telomere Binding Protein

Yao

et al. 2017

J Virol

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Enterovirus 71 (EV71) is an emerging pathogen causing hand, foot, and mouth disease (HFMD) and fatal neurological diseases in infants and young children due to their underdeveloped immunocompetence. EV71 infection can induce cellular apoptosis through a variety of pathways, which promotes EV71 release. The viral protease 3C plays an important role in EV71-induced apoptosis. However, the molecular mechanism responsible for 3C-triggered apoptosis remains elusive. Here, we found that EV71 3C directly interacted with PinX1, a telomere binding protein. Furthermore, 3C cleaved PinX1 at the site of Q50-G51 pair through its protease activity. Overexpression of PinX1 reduced the level of EV71-induced apoptosis and EV71 release, whereas depletion of PinX1 by small interfering RNA promoted apoptosis induced by etoposide and increased EV71 release. Taken together, our study uncovered a mechanism that EV71 utilizes to promote host cell apoptosis through cleavage of cellular protein PinX1 by 3C.IMPORTANCE EV71 3C plays an important role in processing viral proteins and interacting with host cells. In this study, we showed that 3C promoted apoptosis through cleaving PinX1, a telomere binding protein, and that this cleavage facilitated EV71 release. Our study demonstrated that PinX1 plays an important role in EV71 release and revealed a novel mechanism that EV71 utilizes to induce apoptosis. This finding is important in understanding EV71-host cell interactions and has potential impact on understanding other enterovirus-host cell interactions.KEYWORDS enterovirus 71, 3C, PinX1, apoptosis E nterovirus 71 (EV71) is an emerging pathogen that was originally isolated from an infant with central nervous system disease in California (1). Since then, EV71 has caused several large-scale epidemic outbreaks throughout the world, especially in the Asia-Pacific region (2-4). These outbreaks caused significant morbidity and mortality and severely endangered the public health (5). EV71 infection causes hand, foot, and mouth disease (HFMD) and fatal neurological diseases, such as aseptic meningitis, brainstem encephalitis, and neurogenic pulmonary edema (NPE), in infants and young children due to their underdeveloped immunocompetence (6). To date, there are no effective therapeutic medicines or vaccines for EV71.EV71 belongs to the Picornaviridae family with a single positive-stranded RNA genome. Translation of the RNA genome produces a single polyprotein precursor that is subsequently processed into structural (VP1, VP2, VP3, and VP4) and nonstructural (2A, 2B, 2C, 3A, 3B, 3C, and 3D) proteins (7). In addition to its role in viral precursor processing (8), 3C is also involved in a number of biological processes. It has been reported that 3C cleaves cellular CstF-64 protein, which inhibits host RNA processing and polyadenylation (9). Interferon-regulatory factor 7 (IRF7) (10), TIR domain-containing adaptor inducing beta interferon (TRIF) (11) and the TAK1/TAB1/

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Section: Discussionsupporting

confidence: 90%

Enterovirus 71 3C Promotes Apoptosis through Cleavage of PinX1, a Telomere Binding Protein

Yao

et al. 2017

J Virol

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“…For instance, Xi et al (39) studied the interplay between autophagy and apoptosis in human rhabdomyosarcoma cells infected with enterovirus 71. These authors observed that caspase 3, a member of the apoptosis cascade, was an important regulator in autophagosome maturation (LC3B conversion) and, thus, in the relationship between autophagy and apoptosis.…”

Section: Omp33-36 Induces Apoptosis In Human Cells (I) Omp33-36 Prodmentioning

confidence: 99%

The Acinetobacter baumannii Omp33-36 Porin Is a Virulence Factor That Induces Apoptosis and Modulates Autophagy in Human Cells

et al. 2014

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Acinetobacter baumannii is an extracellular opportunistic human pathogen that is becoming increasingly problematic in hospitals. In the present study, we demonstrate that the A. baumannii Omp 33-to 36-kDa protein (Omp33-36) is a porin that acts as a channel for the passage of water. The protein is found on the cell surface and is released along with other porins in the outer membrane vesicles (OMVs). In immune and connective cell tissue, this protein induced apoptosis by activation of caspases and modulation of autophagy, with the consequent accumulation of p62/SQSTM1 (sequestosome 1) and LC3B-II (confirmed by use of autophagy inhibitors). Blockage of autophagy enables the bacterium to persist intracellularly (inside autophagosomes), with the subsequent development of cytotoxicity. Finally, we used macrophages and a mouse model of systemic infection to confirm that Omp33-36 is a virulence factor in A. baumannii. Overall, the study findings show that Omp33-36 plays an important role in the pathogenesis of A. baumannii infections.

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“…It is not excluded that apoptosis may be differentially regulated in ECTV-MOS infected cells depending on the stage and the type of autophagic pathway, which is inhibited. Recently, Xi and colleagues (56) have demonstrated that inhibition of autophagy at the autophagosome formation stage and autophagy execution stage decreased the apoptosis induced by enterovirus 71 (EV71). However, inhibition of autophagy at the stage of autophagosome and lysosome fusion promoted the EV71-induced apoptosis (56).…”

Section: Martyniszyn Et Almentioning

confidence: 99%

“…Recently, Xi and colleagues (56) have demonstrated that inhibition of autophagy at the autophagosome formation stage and autophagy execution stage decreased the apoptosis induced by enterovirus 71 (EV71). However, inhibition of autophagy at the stage of autophagosome and lysosome fusion promoted the EV71-induced apoptosis (56). Our studies revealed that induction of autophagy by rapamycin increased the level of late apoptotic/necrotic cells (Fig.…”

Section: Martyniszyn Et Almentioning

confidence: 99%

Crosstalk Between Autophagy and Apoptosis in RAW 264.7 Macrophages Infected With Ectromelia Orthopoxvirus

et al. 2013

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Several studies have provided evidence that complex relationships between autophagic and apoptotic cell death pathways occur in cancer and virus-infected cells. Previously, we demonstrated that infection of macrophages with Moscow strain of ectromelia virus (ECTV-MOS) induces apoptosis under in vitro and in vivo conditions. Here, we found that autophagy was induced in RAW 264.7 cells during infection with ECTV-MOS. Silencing of beclin 1, an autophagy-related gene, reduced the percentage of late apoptotic cells in virus-infected RAW 264.7 macrophages. Pharmacological modulation of autophagy by wortmannin (inhibitor) or rapamycin (inductor) did not affect or cause increased apoptosis in ECTV-MOS-infected RAW 264.7 cells, respectively. Meantime, blocking apoptosis by a pan-caspase inhibitor, Z-VAD-FMK, increased the formation of autophagosomes in infected macrophages. Taken together, three important points arise from our study. First, autophagy may cooccur with apoptosis in RAW 264.7 cells exposed to ECTV-MOS. Second, at later stages of infection, autophagy may partially participate in the execution of macrophage cell death by enhancing apoptosis. Third, when apoptosis is blocked infected macrophages undergo increased autophagy. Our results provide new information about the relationship between autophagy and apoptosis in ECTV-MOS-infected macrophages.

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The Interplays between Autophagy and Apoptosis Induced by Enterovirus 71

Cited by 61 publications

References 44 publications

Enterovirus 71 3C Promotes Apoptosis through Cleavage of PinX1, a Telomere Binding Protein

Enterovirus 71 3C Promotes Apoptosis through Cleavage of PinX1, a Telomere Binding Protein

The Acinetobacter baumannii Omp33-36 Porin Is a Virulence Factor That Induces Apoptosis and Modulates Autophagy in Human Cells

Crosstalk Between Autophagy and Apoptosis in RAW 264.7 Macrophages Infected With Ectromelia Orthopoxvirus

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