Enterovirus-Induced miR-141 Contributes to Shutoff of Host Protein Translation by Targeting the Translation Initiation Factor eIF4E

Ho, Bing-Ching; Yu, Sung-Liang; Chen, Jeremy J.W.; Chang, Sui‐Yuan; Yan, Bo; Hong, Quan; Singh, Sukhbir; Kao, Chuan-Liang; Chen, Hsuan Yu; Su, Kang-Yi; Li, Ker Chau; Cheng, Chu-Yun; Cheng, Hao Wei; Lee, Jen Yi; Lee, Chun Nan; Yang, Pan‐Chyr

doi:10.1016/j.chom.2010.12.001

Cited by 149 publications

(142 citation statements)

References 43 publications

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“…46 In combination with the higher affinity of 2A to eIF4G over DAP5, 47 this may explain the relatively low changes in VP1 expression when DAP5-C is overexpressed. Although DAP5-C induces dephosphorylation of eIF4E, its effect on enhancement of viral translation may be modest, given that eIF4E is downregulated by microRNA 141 during enteroviral infection 48 and eIF4E dephosphorylation occurs early during infection. 34 However, the generation of DAP5-C, along with 4EBP1, 49 may partially explain the dephosphorylation of eIF4E later during infection, where DAP5-C competes with eIF4E for MNK1 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Cleavage of DAP5 by coxsackievirus B3 2A protease facilitates viral replication and enhances apoptosis by altering translation of IRES-containing genes

Hanson

Qiu

et al. 2015

Cell Death Differ

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Cleavage of eukaryotic translation initiation factor 4G (eIF4G) by enterovirus proteases during infection leads to the shutoff of cellular cap-dependent translation, but does not affect the initiation of cap-independent translation of mRNAs containing an internal ribosome entry site (IRES). Death-associated protein 5 (DAP5), a structural homolog of eIF4G, is a translation initiation factor specific for IRES-containing mRNAs. Coxsackievirus B3 (CVB3) is a positive single-stranded RNA virus and a primary causal agent of human myocarditis. Its RNA genome harbors an IRES within the 5′-untranslated region and is translated by a cap-independent, IRES-driven mechanism. Previously, we have shown that DAP5 is cleaved during CVB3 infection. However, the protease responsible for cleavage, cleavage site and effects on the translation of target genes during CVB3 infection have not been investigated. In the present study, we demonstrated that viral protease 2A but not 3C is responsible for DAP5 cleavage, generating 45-and 52-kDa N-(DAP5-N) and C-terminal (DAP5-C) fragments, respectively. By site-directed mutagenesis, we found that DAP5 is cleaved at amino acid G434. Upon cleavage, DAP5-N largely translocated to the nucleus at the later time points of infection, whereas the DAP5-C largely remained in the cytoplasm. Overexpression of these DAP5 truncates demonstrated that DAP5-N retained the capability of initiating IRES-driven translation of apoptosis-associated p53, but not the prosurvival Bcl-2 (B-cell lymphoma 2) when compared with the full-length DAP5. Similarly, DAP5-N expression promoted CVB3 replication and progeny release; on the other hand, DAP5-C exerted a dominant-negative effect on cap-dependent translation. Taken together, viral protease 2A-mediated cleavage of DAP5 results in the production of two truncates that exert differential effects on protein translation of the IRES-containing genes, leading to enhanced host cell death. Coxsackievirus B3 (CVB3), a primary cause of viral myocarditis, is associated with sudden, unexpected death, 1 dilated cardiomyopathy and heart failure. 2 The CVB3 genome consists of a single open reading frame, which is translated to a polyprotein, and subsequently processed by viral proteases 2A and 3C. Similar to other picornaviruses, the CVB3 genome is linked to a small viral peptide, Vpg, rather than a 7-methyl guanosine cap structure at its 5′ terminus. Thus, CVB3 RNA is translated by a cap-independent mechanism and is driven by an internal ribosome entry site (IRES) harbored in the 5′ untranslated region (5′-UTR). 3,4 Viral proteases actively suppress multiple host cell activities that help the virus evade host defense mechanisms, promote viral replication and promote host cell apoptosis. For example, enterovirus proteases can cleave eukaryotic translation initiation factors 4GI (eIF4GI) 5-7 and eIF4GII. 8,9 Picornavirus proteases have also been reported to cleave other canonical translation initiation factors in the cap-dependent translation initiation complex, such as eIF5B 10 and ...

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Section: Discussionmentioning

confidence: 99%

Cleavage of DAP5 by coxsackievirus B3 2A protease facilitates viral replication and enhances apoptosis by altering translation of IRES-containing genes

Hanson

Qiu

et al. 2015

Cell Death Differ

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show abstract

“…This extracellular viral mRNA expression, respectively. [20][21][22][23][24] Yet another layer of complexity is the ability of some viruses to modulate the levels of host miRNAs. This commonly involves viral suppressor proteins that antagonize the small RNA-directed immunity of the host (reviewed in ref.…”

Section: Microrna Responses To Pathogenic Bacteriamentioning

confidence: 99%

The mammalian microRNA response to bacterial infections

2012

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“…This finding was further solidified by a recent study, which demonstrated that enterovirus 71 (EV71) infection up-regulated miR-141 expression and resulted in a shift from cap-dependent to cap-independent translation initiation by targeting 4E-BP. As EV71 RNA translates through a cap-independent, IRES mechanism, this targeting enhanced EV71 replication (Ho, et al, 2011). Another miRNA, miR-2, has also been reported to utilize a similar mechanism to target the cap structure (Zdanowicz, et al, 2009).…”

Section: The Role Of Micrornas (Mirna) In Translational Controlmentioning

confidence: 99%

“…miRNA modulated repression takes place in processing (P)-bodies that contain decapping enzymes (see discussion in a later section), further supporting the role of miRNA in suppressing capdependent translation initiation . Viruses have been shown to influence the expression of select miRNAs (Ho, et al, 2011, Humphreys, et al, 2005, Lei, et al, 2010, which are often involved in the inhibition of cap-dependent translation (Humphreys, et al, 2005, Walters, et al, 2009 lending to a virally influenced shift to IRESmediated translation. In the early study of the mechanism of translation suppression using an artificial miRNA targeting CXCR4, the cap/4E-BP and the poly-(A) tail of mRNA were all found to play an important role because they are each necessary but not sufficient for full miRNA-mediated repression of translation.…”

Section: The Role Of Micrornas (Mirna) In Translational Controlmentioning

confidence: 99%

See 1 more Smart Citation

Viral Replication Strategies: Manipulation of ER Stress Response Pathways and Promotion of IRES-Dependent Translation

Hanson¹,

Zhang²,

Hemida³

et al. 2013

Viral Replication

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Enterovirus-Induced miR-141 Contributes to Shutoff of Host Protein Translation by Targeting the Translation Initiation Factor eIF4E

Cited by 149 publications

References 43 publications

Cleavage of DAP5 by coxsackievirus B3 2A protease facilitates viral replication and enhances apoptosis by altering translation of IRES-containing genes

Cleavage of DAP5 by coxsackievirus B3 2A protease facilitates viral replication and enhances apoptosis by altering translation of IRES-containing genes

The mammalian microRNA response to bacterial infections

Viral Replication Strategies: Manipulation of ER Stress Response Pathways and Promotion of IRES-Dependent Translation

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