DAP5 associates with eIF2β and eIF4AI to promote Internal Ribosome Entry Site driven translation

Liberman, Noa; Gandin, Valentina; Svitkin, Yuri V.; David, Maya; Virgili, Geneviève; Jaramillo, Maritza; Holčı́k, Martin; Nagar, Bhushan; Kimchi, Adi; Sonenberg, Nahum

doi:10.1093/nar/gkv205

Cited by 95 publications

(110 citation statements)

References 81 publications

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…52,53 Therefore, DAP5-C is incapable of direct interaction with IRES mRNA owing to the lack of eIF4A-binding domain; however, it likely indirectly enhances IRES-driven translation by competing with eIF4E. Thus, DAP5-C may have a dominant-negative effect on cap-dependent translation and indirectly enhance capindependent translation.…”

Section: Figurementioning

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

View full text Add to dashboard Cite

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 ...

show abstract

Section: Figurementioning

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

View full text Add to dashboard Cite

show abstract

“…eIF4G is a scaffold for binding eIF4E, the cap recognition factor; eIF4A, the RNA helicase; eIF3, which recruits the 40S ribosome; and poly(A)-binding protein (PABP). DAP5, however, lacks eIF4G's N terminus, including the eIF4E-and PABP-interacting domains, and is thus incapable of mediating cap-dependent translation (Imataka et al 1997;Levy-Strumpf et al 1997;Yamanaka et al 1997;Liberman et al 2015). Rather, it mediates cap-independent translation through a mechanism involving the recruitment of the ribosome directly to specific mRNAs that contain an internal ribosome entry site (IRES) in their 5 ′ untranslated region (UTR).…”

mentioning

confidence: 99%

“…Rather, it mediates cap-independent translation through a mechanism involving the recruitment of the ribosome directly to specific mRNAs that contain an internal ribosome entry site (IRES) in their 5 ′ untranslated region (UTR). DAP5 stimulates IRES-dependent translation of cellular mRNAs in rabbit reticulocyte lysates (RRLs) but is completely dispensable for capdependent translation (Liberman et al 2015). In cells, DAP5 supports IRES-driven translation of c-Myc, Apaf-1, c-IAP2, and p53 under apoptotic or stress conditions (Henis-Korenblit et al 2002;Nevins et al 2003;Warnakulasuriyarachchi et al 2004;Lewis et al 2008;WeingartenGabbay et al 2014) and, in nonstressed cells, drives IRESmediated translation of Bcl-2 and CDK1 during the mitotic phase of the cell cycle (Marash et al 2008).…”

mentioning

confidence: 99%

Cap-independent translation by DAP5 controls cell fate decisions in human embryonic stem cells

et al. 2016

Self Cite

View full text Add to dashboard Cite

Multiple transcriptional and epigenetic changes drive differentiation of embryonic stem cells (ESCs). This study unveils an additional level of gene expression regulation involving noncanonical, cap-independent translation of a select group of mRNAs. This is driven by death-associated protein 5 (DAP5/eIF4G2/NAT1), a translation initiation factor mediating IRES-dependent translation. We found that the DAP5 knockdown from human ESCs (hESCs) resulted in persistence of pluripotent gene expression, delayed induction of differentiation-associated genes in different cell lineages, and defective embryoid body formation. The latter involved improper cellular organization, lack of cavitation, and enhanced mislocalized apoptosis. RNA sequencing of polysome-associated mRNAs identified candidates with reduced translation efficiency in DAP5-depleted hESCs. These were enriched in mitochondrial proteins involved in oxidative respiration, a pathway essential for differentiation, the significance of which was confirmed by the aberrant mitochondrial morphology and decreased oxidative respiratory activity in DAP5 knockdown cells. Further analysis identified the chromatin modifier HMGN3 as a cap-independent DAP5 translation target whose knockdown resulted in defective differentiation. Thus, DAP5-mediated translation of a specific set of proteins is critical for the transition from pluripotency to differentiation, highlighting the importance of capindependent translation in stem cell fate decisions.

show abstract

“…65 FXR1a-microRNP interacts with p97/DAP5, a non-canonical translation factor that brings in eIF3-40S ribosome subunit in place of eIF4G. [103][104][105][106][107][108][109][110][111][112][113] FXR1a-microRNP also interacts with PARN that binds mRNA 5 0 caps in G0 in place of eIF4E, thus connecting p97-FXR1a-microRNP that is recruited to the 3 0 UTR, with the 5 0 cap to replace the canonical 5 0 -3 0 eIF4E-eIF4G-PABP link. 31 These alternate cap binding and ribosome recruitment factors promote specialized translation of specific poly(A) shortened mRNAs associated with FXR1a-microRNP in quiescent conditions, where canonical translation is reduced.…”

Section: Canonical Translation Mechanismmentioning

confidence: 99%

“…[103][104][105][106] P97 lacks eIF4E and PABP binding sites, but possesses a similar eIF3 binding site to that of canonical translation factor eIF4G, which can recruit eIF3 and thereby, 40S ribosome subunits to initiate translation. 105,107 P97 has been shown to mediate cap independent, IRES driven translation during cellular stress and specific conditions [107][108][109][110][111][112][113] where p97 is recruited via mRNA interactions. P97 mediates cap dependent alternative translation in quiescent conditions, where canonical translation factor eIF4G-that brings in the 40S ribosome subunit to initiate translation-cannot be recruited due to interference with the cap complex by active 4EBPs.…”

mentioning

confidence: 99%

FXR1a-associated microRNP: A driver of specialized non-canonical translation in quiescent conditions

Bukhari

Vasudevan

2017

RNA Biology

View full text Add to dashboard Cite

Eukaryotic protein synthesis is a multifaceted process that requires coordination of a set of translation factors in a particular cellular state. During normal growth and proliferation, cells generally make their proteome via conventional translation that utilizes canonical translation factors. When faced with environmental stress such as growth factor deprivation, or in response to biological cues such as developmental signals, cells can reduce canonical translation. In this situation, cells adapt alternative modes of translation to make specific proteins necessary for required biological functions under these distinct conditions. To date, a number of alternative translation mechanisms have been reported, which include non-canonical, cap dependent translation and cap independent translation such as IRES mediated translation. Here, we discuss one of the alternative modes of translation mediated by a specialized microRNA complex, FXR1a-microRNP that promotes non-canonical, cap dependent translation in quiescent conditions, where canonical translation is reduced due to low mTOR activity.

show abstract

DAP5 associates with eIF2β and eIF4AI to promote Internal Ribosome Entry Site driven translation

Cited by 95 publications

References 81 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

Cap-independent translation by DAP5 controls cell fate decisions in human embryonic stem cells

FXR1a-associated microRNP: A driver of specialized non-canonical translation in quiescent conditions

Contact Info

Product

Resources

About