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Coronavirus infection, ER stress, apoptosis and innate immunity.

Fung TS, Liu DX - Front Microbiol (2014)

Bottom Line: Accumulating evidence from recent studies has shown that induction of ER stress and UPR may constitute a major aspect of coronavirus-host interaction.Activation of the three branches of UPR modulates a wide variety of signaling pathways, such as mitogen-activated protein (MAP) kinase activation, autophagy, apoptosis, and innate immune response.In this review, we summarize the current knowledge on coronavirus-induced ER stress and UPR activation, with emphasis on their cross-talking to apoptotic signaling.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University Singapore, Singapore.

ABSTRACT
The replication of coronavirus, a family of important animal and human pathogens, is closely associated with the cellular membrane compartments, especially the endoplasmic reticulum (ER). Coronavirus infection of cultured cells was previously shown to cause ER stress and induce the unfolded protein response (UPR), a process that aims to restore the ER homeostasis by global translation shutdown and increasing the ER folding capacity. However, under prolonged ER stress, UPR can also induce apoptotic cell death. Accumulating evidence from recent studies has shown that induction of ER stress and UPR may constitute a major aspect of coronavirus-host interaction. Activation of the three branches of UPR modulates a wide variety of signaling pathways, such as mitogen-activated protein (MAP) kinase activation, autophagy, apoptosis, and innate immune response. ER stress and UPR activation may therefore contribute significantly to the viral replication and pathogenesis during coronavirus infection. In this review, we summarize the current knowledge on coronavirus-induced ER stress and UPR activation, with emphasis on their cross-talking to apoptotic signaling.

No MeSH data available.


Related in: MedlinePlus

Working model of PKR/PERK-eIF2α-ATF4-GADD153 pathway activation during coronavirus infection, using IBV as an example. Phosphorylation of eIF2α by PERK and PKR induces the expression of ATF4, ATF3, and GADD153. GADD153 exerts its pro-apoptotic activities via suppressing Bcl2 and ERKs by inducing TRIB3. The potential induction of DUSP1 by ATF3 may modulate phosphorylation of p38 and JNK, thus regulating IBV-induced apoptosis and cytokine production. The translation attenuation due to eIF2α activation can also lead to reduced inhibition of IκBα on NF-κB, which in turn promote cytokine production. Pointed arrows indicate activation, and blunt-ended lines indicate inhibition. The question mark indicates hypothetical mechanism.
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Figure 3: Working model of PKR/PERK-eIF2α-ATF4-GADD153 pathway activation during coronavirus infection, using IBV as an example. Phosphorylation of eIF2α by PERK and PKR induces the expression of ATF4, ATF3, and GADD153. GADD153 exerts its pro-apoptotic activities via suppressing Bcl2 and ERKs by inducing TRIB3. The potential induction of DUSP1 by ATF3 may modulate phosphorylation of p38 and JNK, thus regulating IBV-induced apoptosis and cytokine production. The translation attenuation due to eIF2α activation can also lead to reduced inhibition of IκBα on NF-κB, which in turn promote cytokine production. Pointed arrows indicate activation, and blunt-ended lines indicate inhibition. The question mark indicates hypothetical mechanism.

Mentions: Interestingly, the mRNAs of certain genes contain small ORFs in their 5′ UTR and bypass the eIF2α-dependent translation block. One of these is the activating transcription factor 4 (ATF4), which is preferentially translated under ISR. ATF4 in turn transactivates genes involved in amino acid metabolism, redox reactions, and stress response. One of ATF4’s target genes is the growth arrest and DNA damage-inducible protein 153 (GADD153, also known as C/EBP homologous protein, or CHOP). GADD153 induces the growth arrest and DNA damage-inducible protein 34 (GADD34), which recruits protein phosphatase 1 (PP1) to dephosphorylate eIF2α and release the translation block. To this end, if ER stress is resolved, normal protein synthesis can be resumed. However, if ER stress persists, GADD153 can induce apoptosis by suppressing the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) and inducing the pro-apoptotic proteins such as Bcl-2-interacting mediator of cell death (Bim; Puthalakath et al., 2007). GADD153 also activates ER oxidoreductin-1α (ERO1α), which encodes an ER oxidase. The increase protein influx to a hyper-oxidizing ER aggravates ER stress and induces apoptosis (Marciniak et al., 2004; Figure 3).


Coronavirus infection, ER stress, apoptosis and innate immunity.

Fung TS, Liu DX - Front Microbiol (2014)

Working model of PKR/PERK-eIF2α-ATF4-GADD153 pathway activation during coronavirus infection, using IBV as an example. Phosphorylation of eIF2α by PERK and PKR induces the expression of ATF4, ATF3, and GADD153. GADD153 exerts its pro-apoptotic activities via suppressing Bcl2 and ERKs by inducing TRIB3. The potential induction of DUSP1 by ATF3 may modulate phosphorylation of p38 and JNK, thus regulating IBV-induced apoptosis and cytokine production. The translation attenuation due to eIF2α activation can also lead to reduced inhibition of IκBα on NF-κB, which in turn promote cytokine production. Pointed arrows indicate activation, and blunt-ended lines indicate inhibition. The question mark indicates hypothetical mechanism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4060729&req=5

Figure 3: Working model of PKR/PERK-eIF2α-ATF4-GADD153 pathway activation during coronavirus infection, using IBV as an example. Phosphorylation of eIF2α by PERK and PKR induces the expression of ATF4, ATF3, and GADD153. GADD153 exerts its pro-apoptotic activities via suppressing Bcl2 and ERKs by inducing TRIB3. The potential induction of DUSP1 by ATF3 may modulate phosphorylation of p38 and JNK, thus regulating IBV-induced apoptosis and cytokine production. The translation attenuation due to eIF2α activation can also lead to reduced inhibition of IκBα on NF-κB, which in turn promote cytokine production. Pointed arrows indicate activation, and blunt-ended lines indicate inhibition. The question mark indicates hypothetical mechanism.
Mentions: Interestingly, the mRNAs of certain genes contain small ORFs in their 5′ UTR and bypass the eIF2α-dependent translation block. One of these is the activating transcription factor 4 (ATF4), which is preferentially translated under ISR. ATF4 in turn transactivates genes involved in amino acid metabolism, redox reactions, and stress response. One of ATF4’s target genes is the growth arrest and DNA damage-inducible protein 153 (GADD153, also known as C/EBP homologous protein, or CHOP). GADD153 induces the growth arrest and DNA damage-inducible protein 34 (GADD34), which recruits protein phosphatase 1 (PP1) to dephosphorylate eIF2α and release the translation block. To this end, if ER stress is resolved, normal protein synthesis can be resumed. However, if ER stress persists, GADD153 can induce apoptosis by suppressing the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) and inducing the pro-apoptotic proteins such as Bcl-2-interacting mediator of cell death (Bim; Puthalakath et al., 2007). GADD153 also activates ER oxidoreductin-1α (ERO1α), which encodes an ER oxidase. The increase protein influx to a hyper-oxidizing ER aggravates ER stress and induces apoptosis (Marciniak et al., 2004; Figure 3).

Bottom Line: Accumulating evidence from recent studies has shown that induction of ER stress and UPR may constitute a major aspect of coronavirus-host interaction.Activation of the three branches of UPR modulates a wide variety of signaling pathways, such as mitogen-activated protein (MAP) kinase activation, autophagy, apoptosis, and innate immune response.In this review, we summarize the current knowledge on coronavirus-induced ER stress and UPR activation, with emphasis on their cross-talking to apoptotic signaling.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University Singapore, Singapore.

ABSTRACT
The replication of coronavirus, a family of important animal and human pathogens, is closely associated with the cellular membrane compartments, especially the endoplasmic reticulum (ER). Coronavirus infection of cultured cells was previously shown to cause ER stress and induce the unfolded protein response (UPR), a process that aims to restore the ER homeostasis by global translation shutdown and increasing the ER folding capacity. However, under prolonged ER stress, UPR can also induce apoptotic cell death. Accumulating evidence from recent studies has shown that induction of ER stress and UPR may constitute a major aspect of coronavirus-host interaction. Activation of the three branches of UPR modulates a wide variety of signaling pathways, such as mitogen-activated protein (MAP) kinase activation, autophagy, apoptosis, and innate immune response. ER stress and UPR activation may therefore contribute significantly to the viral replication and pathogenesis during coronavirus infection. In this review, we summarize the current knowledge on coronavirus-induced ER stress and UPR activation, with emphasis on their cross-talking to apoptotic signaling.

No MeSH data available.


Related in: MedlinePlus