Glucocorticoids Prevent Enterovirus 71 Capsid Protein VP1 Induced Calreticulin Surface Exposure by Alleviating Neuronal ER Stress

Hu, Dandan; Mai, Jianning; He, Liang; Li, Peiqing; Chen, Wenxiong; Yan, Jian-jiang; Zhu, Wei; Deng, Li; Wei, Dan; Liu, Di-Hui; Yang, Sen; Ye, Zhibin

doi:10.1007/s12640-016-9670-0

Cited by 21 publications

(20 citation statements)

References 42 publications

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“…In the present study, we demonstrated that VP1 plays a promotive role in MSC autophagy (Fig. 2), which is consistent with our previous findings(25). However, the effect of VP1-induced autophagy on MSC survival still remains unclear because autophagy plays dual roles in the nervous system.…”

Section: Discussionsupporting

confidence: 94%

“…Interestingly, in an EV71-infected mouse model, VP1 was found co-localized with LC3 and/or autophagosome-like vesicles in neurons, and VP1 expression was positively correlated with LC3-II expression, aggregation and autophagosome formation(24). Upregulation of LC3-II expression was also observed in VP1-transfected HEK293 cells(25). Considering the regulatory role of VP1 in both MSC autophagy and PMP22 expression (Fig.…”

Section: Discussionmentioning

confidence: 96%

“…EV71 has been shown to induce autophagy in infected human rhabdomyosarcoma and neuroblastoma cells(23, 24). Our previous study demonstrates that EV71 structural viral protein 1 (VP1) also induces autophagy in cultured primary EV71-infected brainstem neurons, which can be inhibited by endoplasmic reticulum (ER) stress inhibitor salubrinal (SAL)(25), suggesting an essential role of ER stress in VP1-induced autophagy.…”

Section: Introductionmentioning

confidence: 99%

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Enterovirus 71 structural viral protein 1 promotes mouse Schwann cell autophagy via endoplasmic reticulum stress-mediated peripheral myelin protein 22 upregulation

Yang

et al. 2018

Preprint

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1 autophagy via endoplasmic reticulum stress-mediated peripheral myelin protein 2 22 upregulation 3 4 Abstract 27 Enterovirus 71 (EV71) accounts for the majority of hand, foot and mouth disease-28 related deaths due to fatal neurological complications. The clinical observations and 29 animal models found the early invasion of nervous system, and the demyelinating 30 phenomenon was observed. As one of the receptors of EV71 structural viral protein 1 31 (VP1), SCARB2 mainly exists on the myelin sheath. EV71 VP1 can promote viral 32 replication through inducing autophagy in neuron cells. This study aims to investigate 33 the role and mechanism of VP1 in autophagy of mouse Schwann cells (MSCs). An 34 EV71 VP1-expressing vector (pEGFP-C3-VP1) was generated and transfected into 35 MSCs. Transmission electron microscopy (TEM) and Western blot analysis of the 36 autophagy marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) 37 were used to assess autophagy in the cells. Real-time PCR and immunofluorescent 38 staining were performed to determine the expression of PMP22. Small interfering 39 RNA against PMP22 was employed to investigate the role of PMP22 in MSCs 40 autophagy. Selective endoplasmic reticulum (ER) stress inhibitor salubrinal (SAL) 41 was employed to determine whether PMP22 is mediated by ER stress. Our results 42 demonstrated that VP1 played a promotive role in MSC autophagy. Overexpression of 43 VP1 upregulated PMP22. PMP22 deficiency downregulated LC3B and thus inhibited 44 autophagy. Furthermore, PMP22 expression was significantly suppressed by SAL. 45 VP1 promotes MSC autophagy through upregulating ER stress-mediated PMP22 46 expression. VP1/ER stress/ PMP22 axis in autophagy may be a potential therapeutic 47 target for EV71 infection-induced fatal neuronal damage.48 49 Key words: Enterovirus 71 structural viral protein 1; autophagy; endoplasmic 50 reticulum stress; peripheral myelin protein 22 51

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Enterovirus 71 structural viral protein 1 promotes mouse Schwann cell autophagy via endoplasmic reticulum stress-mediated peripheral myelin protein 22 upregulation

Yang

et al. 2018

Preprint

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“…Some reported cases of neuronophagia may be neurophagy. For example, there are multiple reports of neuronophagia in brains infected with different viruses, including the hand‐foot‐and‐mouth disease enterovirus 71, where viral infection resulted in exposure of calreticulin on neurons that were apparently eaten alive by glia . This raises the possibility that one of the functions of neuronophagia and neurophagy is to remove and destroy virally infected neurons to prevent spread of the virus.…”

Section: Neuronophagiamentioning

confidence: 99%

Neurophagy, the phagocytosis of live neurons and synapses by glia, contributes to brain development and disease

2017

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It was previously thought that neurons were phagocytosed only when dead or dying. However, it is increasingly clear that viable synapses, dendrites, axons and whole neurons can be phagocytosed alive (defined here as neurophagy), and this may contribute to a wide range of developmental, physiological and pathological processes. Phagocytosis of live synapses, dendrites and axons by glia contributes to experience‐dependent sculpting of neuronal networks during development, but excessive phagocytosis of synapses may contribute to pathology in Alzheimer's disease, schizophrenia and ageing. Neurons can expose phosphatidylserine or calreticulin, which act as ‘eat me’ signals provoking phagocytosis via microglial receptors, whereas sialylation of neuronal surfaces acts as a ‘don't eat me’ signal that inhibits phagocytosis and desialylation can provoke phagocytosis. Opsonins, such as complement components and apolipoproteins, are released during inflammation and enhance engulfment. Phagocytosis of neurons is seen in multiple human diseases, but it is as yet unclear whether inhibition of phagocytosis will be beneficial in treating neurological diseases. Here we review the signals regulating glial phagocytosis of live neurons and synapses, and the involvement of this phagocytosis in development and disease.

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“…Virus infection could induce autophagy, and many viral proteins can induce autophagy also [37][38][39][40]. A recent study showed that neither 2B, 2C, 3A, 3B, 3AB, 3C nor 3D could trigger autophagy individually [7].…”

Section: Discussionmentioning

confidence: 99%

Characteristics of Autophagy Induced by Enterovirus71 (EV71) Viral Protein

Li¹,

Jinxue²,

Liu³

et al. 2018

J Trop Dis

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Hand, Foot and Mouth Disease (HFMD) is a type of infectious disease that is more commonly seen in children under the age of 6 years. It was first reported in New Zealand in 1957, and then outbreaks occurred in Europe, America and Asia. In recent years, the incidence of HFMD in China is also on the rise. HFMD was caused by Coxsackievirus A16 (CVA16) and Human Enterovirus 71 (EV71) and other virus. CVA16 usually causes mild cases and is less harmful, while EV71 infection causes not only mild cases, but also severe and fatal cases; it has become a cause of concern. The mechanism of HFMD caused by EV71 virus is not completely clear. After it infects host cells, the EV71 virus genome undergoes replication, translation, assembly, and the release of virosomes. Some studies have reported that EV71 could induce host cell autophagy. Autophagy is a cellular process necessary for the lysosomal degradation and recycling of proteins and entire organelles. It can act as not only a defense mechanism to prevent environmental damage to cells, also induce cell death in eukaryotes. To explore the correlation and characteristics of EV71 virus, EV71 viral protein and autophagy, we used EV71 and recombinant plasmid pcDNA3.1 (+)-HA-X to infect human 293T cells, and we found that autophagy could be induced by EV71. With the prolongation of infection, autophagy presents a dynamic trend. And the protein that causes autophagy is structural protein VP1 and non-structural protein 2A.

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Glucocorticoids Prevent Enterovirus 71 Capsid Protein VP1 Induced Calreticulin Surface Exposure by Alleviating Neuronal ER Stress

Cited by 21 publications

References 42 publications

Enterovirus 71 structural viral protein 1 promotes mouse Schwann cell autophagy via endoplasmic reticulum stress-mediated peripheral myelin protein 22 upregulation

Enterovirus 71 structural viral protein 1 promotes mouse Schwann cell autophagy via endoplasmic reticulum stress-mediated peripheral myelin protein 22 upregulation

Neurophagy, the phagocytosis of live neurons and synapses by glia, contributes to brain development and disease

Characteristics of Autophagy Induced by Enterovirus71 (EV71) Viral Protein

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