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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

Schematic diagram showing the replication cycle of coronavirus and the stages in which ER stress may be induced during coronavirus infection. Infection starts with receptor binding and entry by membrane fusion. After uncoating, the genomic RNA is used as a template to synthesize progeny genomes and a nested set of subgenomic RNAs. The replication transcription centers are closely associated with DMVs, which are proposed to be adopted from the modified ER, possibly by the combined activities of non-structural proteins nsp3, nsp4, and nsp6. The S, E, and M proteins are synthesized and anchored on the ER, whereas the N protein is translated in the cytosol. Assembly takes place in the ERGIC and mature virions are released via smooth-walled vesicles by exocytosis. The three stages that presumably induce ER stress are highlighted with numbered star signs, namely: (1) formation of DMVs, (2) massive production and modification of structural proteins, and (3) depletion of ER membrane during budding.
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Figure 1: Schematic diagram showing the replication cycle of coronavirus and the stages in which ER stress may be induced during coronavirus infection. Infection starts with receptor binding and entry by membrane fusion. After uncoating, the genomic RNA is used as a template to synthesize progeny genomes and a nested set of subgenomic RNAs. The replication transcription centers are closely associated with DMVs, which are proposed to be adopted from the modified ER, possibly by the combined activities of non-structural proteins nsp3, nsp4, and nsp6. The S, E, and M proteins are synthesized and anchored on the ER, whereas the N protein is translated in the cytosol. Assembly takes place in the ERGIC and mature virions are released via smooth-walled vesicles by exocytosis. The three stages that presumably induce ER stress are highlighted with numbered star signs, namely: (1) formation of DMVs, (2) massive production and modification of structural proteins, and (3) depletion of ER membrane during budding.

Mentions: Coronavirus infection starts with receptor binding via the S protein (Figure 1). The S proteins of most coronaviruses are cleaved by host protease into two functional subunits: an N-terminal receptor binding domain (S1) and a C-terminal domain (S2) responsible for membrane fusion (Huang et al., 2006; Qiu et al., 2006; Yamada et al., 2009). The interaction between the cell surface receptor and the S1 subunit is the major determinant of the tropism of coronaviruses (Kuo et al., 2000). Upon receptor binding of S1, a conformational change is triggered in the S2 subunit, exposing its hidden fusion peptide for insertion into the cellular membrane. This is followed by the packing of the two heptad repeats in the three monomers into a six-helix bundle fusion core. This close juxtaposition of the viral and cellular membrane enables fusion of the lipid bilayers, and the viral nucleocapsid is thus delivered into the cytoplasm (Masters, 2006).


Coronavirus infection, ER stress, apoptosis and innate immunity.

Fung TS, Liu DX - Front Microbiol (2014)

Schematic diagram showing the replication cycle of coronavirus and the stages in which ER stress may be induced during coronavirus infection. Infection starts with receptor binding and entry by membrane fusion. After uncoating, the genomic RNA is used as a template to synthesize progeny genomes and a nested set of subgenomic RNAs. The replication transcription centers are closely associated with DMVs, which are proposed to be adopted from the modified ER, possibly by the combined activities of non-structural proteins nsp3, nsp4, and nsp6. The S, E, and M proteins are synthesized and anchored on the ER, whereas the N protein is translated in the cytosol. Assembly takes place in the ERGIC and mature virions are released via smooth-walled vesicles by exocytosis. The three stages that presumably induce ER stress are highlighted with numbered star signs, namely: (1) formation of DMVs, (2) massive production and modification of structural proteins, and (3) depletion of ER membrane during budding.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Schematic diagram showing the replication cycle of coronavirus and the stages in which ER stress may be induced during coronavirus infection. Infection starts with receptor binding and entry by membrane fusion. After uncoating, the genomic RNA is used as a template to synthesize progeny genomes and a nested set of subgenomic RNAs. The replication transcription centers are closely associated with DMVs, which are proposed to be adopted from the modified ER, possibly by the combined activities of non-structural proteins nsp3, nsp4, and nsp6. The S, E, and M proteins are synthesized and anchored on the ER, whereas the N protein is translated in the cytosol. Assembly takes place in the ERGIC and mature virions are released via smooth-walled vesicles by exocytosis. The three stages that presumably induce ER stress are highlighted with numbered star signs, namely: (1) formation of DMVs, (2) massive production and modification of structural proteins, and (3) depletion of ER membrane during budding.
Mentions: Coronavirus infection starts with receptor binding via the S protein (Figure 1). The S proteins of most coronaviruses are cleaved by host protease into two functional subunits: an N-terminal receptor binding domain (S1) and a C-terminal domain (S2) responsible for membrane fusion (Huang et al., 2006; Qiu et al., 2006; Yamada et al., 2009). The interaction between the cell surface receptor and the S1 subunit is the major determinant of the tropism of coronaviruses (Kuo et al., 2000). Upon receptor binding of S1, a conformational change is triggered in the S2 subunit, exposing its hidden fusion peptide for insertion into the cellular membrane. This is followed by the packing of the two heptad repeats in the three monomers into a six-helix bundle fusion core. This close juxtaposition of the viral and cellular membrane enables fusion of the lipid bilayers, and the viral nucleocapsid is thus delivered into the cytoplasm (Masters, 2006).

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