A second eIF4E protein in Schizosaccharomyces pombe has distinct eIF4G-binding properties

The expression of the ubiquitin-like molecule ISG15 and protein modification by ISG15 (ISGylation) are strongly activated by interferon, genotoxic stress, and pathogen infection, suggesting that ISG15 plays an important role in innate immune responses. 4EHP is an mRNA 5 cap structure-binding protein and acts as a translation suppressor by competing with eIF4E for binding to the cap structure. Here, we report that 4EHP is modified by ISG15 and ISGylated 4EHP has a much higher cap structure-binding activity. These data suggest that ISGylation of 4EHP may play an important role in cap structuredependent translation control in immune responses.Supplemental material is available at http://www.genesdev.org.Received July 19, 2006; revised version accepted December 19, 2006. ISG15 was the first reported ubiquitin-like modifier (ubl) (Haas et al. 1987). It forms covalent conjugates with cellular proteins similar to protein ubiquitylation (Loeb and Haas 1992). ISG15 expression and protein modification by ISG15 (ISGylation) are strongly activated by Type I interferon (IFN) (Farrell et al. 1979;Loeb and Haas 1992). IFNs are critical cytokines involved in innate immune responses (Garcia-Sastre and Biron 2006). These facts suggest that ISG15 modification may modulate certain immune responses related to pathogen infections and various stresses. Similar to protein ubiquitylation, ISGylation is also regulated by a set of enzymes. UBE1L is an ISG15 E1 enzyme, which shows high homology with the ubiquitin E1 (Yuan and Krug 2001). USP18 (UBP43) has been identified as a deISGylating isopeptidase (Malakhov et al. 2002). Recently, ubiquitin E2 enzymes UbcH6 and UbcH8 have been determined to function also as ISG15 conjugating enzymes (Kim et al. 2004;Zhao et al. 2004;. UbcH8 is reported to interact with several ubiquitin E3 ligases to mediate protein ubiquitylation . The fact that UbcH8 functions as a dual E2 enzyme for both ubiquitin and ISG15 raises the possibility that some UbcH8-interacting ubiquitin E3 ligases can function as an ISG15 E3 ligase. In fact, we have recently reported that the UbcH8 partner Efp ubiquitin ligase functions as an E3 for 14-3-3 ISGylation (Zou and Zhang 2006).The binding of eukaryotic translation initiation factor 4F (eIF4F) to the mRNA 5Ј cap structure is the rate-limiting step of cap structure-dependent translation initiation in eukaryotes (Gingras et al. 1999). eIF4F contains cap-binding protein eIF4E, scaffold protein eIF4G, and RNA helicase eIF4A. The interaction between eIF4E and eIF4G results in a conformational change of both proteins and enhances the association between eIF4E and the RNA cap structure (Gross et al. 2003). There are three eIF4E-family members in mammals termed eIF4E-1 (eIF4E), eIF4E-2 (4EHP and 4E-LP), and eIF4E-3 (Rom et al. 1998;Joshi et al. 2004). Like prototypical eIF4E, 4EHP is expressed ubiquitously; however, expression of eIF4E-3 is detected only in heart, skeletal muscle, lung, and spleen (Joshi et al. 2004). Similar to eIF4E, both 4EHP and eIF4E-3 bind to the RNA 5Ј cap...

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“…Schizosaccharomyces pombe also has a 4EHP-like protein (eIF4E2, encoded by tif452) (Ptushkina et al 2001). It is not essential for S. Pombe.…”

Section: Isgylation Enhances the Function Of 4ehp In Translational Comentioning

confidence: 99%

ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHP

Okumura¹,

Zou²,

Zhang³

2007

Genes Dev.

159

142

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“…Drosophila melanogaster has eight isoforms that show distinct patterns of expression during embryogenesis (Hernández et al 2005). Distinct variant eIF4E-eIF4G interactions are thus expected and observed (Ptushkina et al 2001). Not all homologs of eIF4E have a role in constitutive translation initiation (Rhoads 2009); they may function as competitive inhibitors of eIF4G recruitment and as scaffolds for interactions with other potential regulatory proteins (Groppo and Richter 2009;Blewett and Goldstrohm 2012;Gosselin et al 2013).…”

Section: Introductionmentioning

confidence: 99%

eIF4F-like complexes formed by cap-binding homolog TbEIF4E5 with TbEIF4G1 or TbEIF4G2 are implicated in post-transcriptional regulation in Trypanosoma brucei

Freire

Vashisht

Malvezzi

et al. 2014

RNA

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Members of the eIF4E mRNA cap-binding family are involved in translation and the modulation of transcript availability in other systems as part of a three-component complex including eIF4G and eIF4A. The kinetoplastids possess four described eIF4E and five eIF4G homologs. We have identified two new eIF4E family proteins in Trypanosoma brucei, and define distinct complexes associated with the fifth member, TbEIF4E5. The cytosolic TbEIF4E5 protein binds cap 0 in vitro. TbEIF4E5 was found in association with two of the five TbEIF4Gs. TbIF4EG1 bound TbEIF4E5, a 47.5-kDa protein with two RNA-binding domains, and either the regulatory protein 14-3-3 II or a 117.5-kDa protein with guanylyltransferase and methyltransferase domains in a potentially dynamic interaction. The TbEIF4G2/TbEIF4E5 complex was associated with a 17.9-kDa hypothetical protein and both 14-3-3 variants I and II. Knockdown of TbEIF4E5 resulted in the loss of productive cell movement, as evidenced by the inability of the cells to remain in suspension in liquid culture and the loss of social motility on semisolid plating medium, as well as a minor reduction of translation. Cells appeared lethargic, as opposed to compromised in flagellar function per se. The minimal use of transcriptional control in kinetoplastids requires these organisms to implement downstream mechanisms to regulate gene expression, and the TbEIF4E5/TbEIF4G1/117.5-kDa complex in particular may be a key player in that process. We suggest that a pathway involved in cell motility is affected, directly or indirectly, by one of the TbEIF4E5 complexes.

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“…eIF4E2, a homologue of eIF4E, can bind to the cap structure of an mRNA but does not interact with eIF4G (23,24) and thus can act as a translational repressor by competing with eIF4E. eIF4E2-knockout mice died within a few hours after birth, with an increase in general translation in brain tissues (25).…”

mentioning

confidence: 99%

Tristetraprolin Recruits Eukaryotic Initiation Factor 4E2 To Repress Translation of AU-Rich Element-Containing mRNAs

Tao

Gao

2015

Molecular and Cellular Biology

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b Tristetraprolin (TTP) regulates the expression of AU-rich element-containing mRNAs through promoting the degradation and repressing the translation of target mRNA. While the mechanism for promoting target mRNA degradation has been extensively studied, the mechanism underlying translational repression is not well established. Here, we show that TTP recruits eukaryotic initiation factor 4E2 (eIF4E2) to repress target mRNA translation. TTP interacted with eIF4E2 but not with eIF4E. Overexpression of eIF4E2 enhanced TTP-mediated translational repression, and downregulation of endogenous eIF4E2 or overexpression of a truncation mutant of eIF4E2 impaired TTP-mediated translational repression. Overexpression of an eIF4E2 mutant that lost the cap-binding activity also impaired TTP's activity, suggesting that the cap-binding activity of eIF4E2 is important in TTPmediated translational repression. We further show that TTP promoted eIF4E2 binding to target mRNA. These results imply that TTP recruits eIF4E2 to compete with eIF4E to repress the translation of target mRNA. This notion is supported by the finding that downregulation of endogenous eIF4E2 increased the production of tumor necrosis factor alpha (TNF-␣) protein without affecting the mRNA levels in THP-1 cells. Collectively, these results uncover a novel mechanism by which TTP represses target mRNA translation.T ristetraprolin (TTP) plays important roles in immunity, development, and tumorigenesis by posttranscriptionally regulating the expression of a variety of genes (1). For example, TTP regulates the expression of tumor necrosis factor alpha (TNF-␣) (2). Knockout of TTP in mice results in TNF-␣ excess and causes severe immune disorders (2, 3).TTP specifically recognizes AU-rich elements (AREs), which are cis elements with tandem AUUUA-like motifs in a context rich in A and/or U, mainly located in the 3= untranslated region (3= UTR) of the mRNAs of stringently regulated genes, such as cytokine and growth factor genes and proto-oncogenes (4, 5). TTP directly binds to ARE motifs and recruits cellular mRNA decay enzymes, including the deadenylase complex CCR4-NOT, decapping complex DCP1a/DCP2, 3=-5= exoribonuclease complex exosome, and 5=-3= exoribonuclease Xrn1, to degrade target mRNAs (6)(7)(8)(9)(10)(11)(12)(13)(14). This activity of TTP is regulated by phosphorylation modification (6-14). There is increasing evidence suggesting that TTP also regulates the translation of target mRNAs. It has been reported elsewhere that TTP associates with polysomes (15, 16) and that a TTP-interacting protein, cullin 4B, promotes the loading of TTP-associated TNF-␣ mRNA complex onto polysomes (17). Recently, Qi et al. reported that TTP inhibits the translation of TNF-␣ in an ARE-dependent manner and the RNA helicase RCK is involved in this process (18). In addition, Tiedje et al. reported that TTP represses the translation of TNF-␣ through competing with HuR to bind to ARE (19). Nonetheless, detailed mechanisms underlying TTP-mediated translational repression are not well esta...

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A second eIF4E protein in Schizosaccharomyces pombe has distinct eIF4G-binding properties

Cited by 36 publications

References 32 publications

ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHP

ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHP

eIF4F-like complexes formed by cap-binding homolog TbEIF4E5 with TbEIF4G1 or TbEIF4G2 are implicated in post-transcriptional regulation in Trypanosoma brucei

Tristetraprolin Recruits Eukaryotic Initiation Factor 4E2 To Repress Translation of AU-Rich Element-Containing mRNAs

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