The eIF3 Interactome Reveals the Translasome, a Supercomplex Linking Protein Synthesis and Degradation Machineries

Sha, Zhe; Brill, Laurence M.; Cabrera, Rodrigo; Kleifeld, Oded; Scheliga, Judith; Glickman, Michael S.; Chang, Eric C.; Wolf, Dieter A

doi:10.1016/j.molcel.2009.09.026

Cited by 123 publications

(142 citation statements)

References 75 publications

(105 reference statements)

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“…A sizable number of newly synthesized polypeptides (NSPs) are incorrectly folded (i.e., defective ribosomal products [DRiPs] in yeast) and undergo ubiquitin-dependent cotranslational degradation (14,15). Multimeric complexes containing the eukaryotic translation initiation factor 3 (eIF3) and proteasomal components have been suggested to regulate degradation of NSPs in yeast (16). However, the mechanism underlying regulation of the stability of NSPs in mammals remains uncharacterized.…”

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confidence: 99%

Degradation of Newly Synthesized Polypeptides by Ribosome-Associated RACK1/c-Jun N-Terminal Kinase/Eukaryotic Elongation Factor 1A2 Complex

Gandin

Gutierrez

Brill

et al. 2013

Molecular and Cellular Biology

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dFolding of newly synthesized polypeptides (NSPs) into functional proteins is a highly regulated process. Rigorous quality control ensures that NSPs attain their native fold during or shortly after completion of translation. Nonetheless, signaling pathways that govern the degradation of NSPs in mammals remain elusive. We demonstrate that the stress-induced c-Jun N-terminal kinase (JNK) is recruited to ribosomes by the receptor for activated protein C kinase 1 (RACK1). RACK1 is an integral component of the 40S ribosome and an adaptor for protein kinases. Ribosome-associated JNK phosphorylates the eukaryotic translation elongation factor 1A isoform 2 (eEF1A2) on serines 205 and 358 to promote degradation of NSPs by the proteasome. These findings establish a role for a RACK1/JNK/eEF1A2 complex in the quality control of NSPs in response to stress.

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confidence: 99%

Degradation of Newly Synthesized Polypeptides by Ribosome-Associated RACK1/c-Jun N-Terminal Kinase/Eukaryotic Elongation Factor 1A2 Complex

Gandin

Gutierrez

Brill

et al. 2013

Molecular and Cellular Biology

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“…eIF3 is a heteromultimeric protein composed of 6 subunits in Saccharomyces cerevisiae (12) and 13 subunits in mammals, 6 of which (a, b, c, e, f, and h) make up a functional core (13,14). It forms a multifactor complex with eIF1, eIF5, and the eIF2⅐GTP⅐Met-tRNA ternary complex that binds to the 40 S ribosomal subunit to form the 43 S preinitiation complex (PIC).…”

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confidence: 99%

Expression of Truncated Eukaryotic Initiation Factor 3e (eIF3e) Resulting from Integration of Mouse Mammary Tumor Virus (MMTV) Causes a Shift from Cap-dependent to Cap-independent Translation

Chiluiza

Bargo

Callahan

et al. 2011

Journal of Biological Chemistry

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Integration of mouse mammary tumor virus (MMTV) at the common integration site Int6 occurs in the gene encoding eIF3e, the p48 subunit of translation initiation factor eIF3. Integration is at any of several introns of the Eif3e gene and causes the expression of truncated Eif3e mRNAs. Ectopic expression of the truncated eIF3e protein resulting from integration at intron 5 (3e5) induces malignant transformation, but by an unknown mechanism. Because eIF3e makes up at least part of the binding site for eIF4G, we examined the effects of 3e5 expression on protein synthesis. We developed an NIH3T3 cell line that contains a single copy of the 3e5 sequence at a predetermined genomic site. Co-immunoprecipitation indicated diminished binding of eIF3 to eIF4G, signifying a reduction in recruitment of the mRNA-unwinding machinery to the 43 S preinitiation complex. Cell growth and overall protein synthesis were decreased. Translation driven by the eIF4G-independent hepatitis C virus internal ribosome entry sequence (HCV IRES) in a bicistronic mRNA was increased relative to cap-dependent translation. Endogenous mRNAs encoding XIAP, c-Myc, CYR61, and Pim-1, which are translated in a cap-independent manner, were shifted to heavier polysomes whereas mRNAs encoding GAPDH, actin, L32, and L34, which are translated in a cap-dependent manner, were shifted to lighter polysomes. We propose that expression of 3e5 diminishes eIF4G interaction with eIF3 and causes abnormal gene expression at the translational level. The correlation between up-regulation of cap-independent translation and MMTV-induced tumorigenesis contrasts with the well established model for malignant transformation involving up-regulation of highly cap-dependent translation.

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“…Consistent with this model, eEF1A has also been involved in cotranslational ubiquitination [48]. Notably, eEF1A and TBP7, both TRAP1 client proteins, have been found in complex with the translation initiation factor IF3, taking part in the so-called "translasome", in which factors involved in translation initiation, ribosome biogenesis, translation elongation, quality control, and transport are physically linked to facilitate efficient protein synthesis [49].…”

Section: Trap1 Regulation Of Tumour Cell Metabolism Is Based On Attenmentioning

confidence: 58%

ER stress protection in cancer cells: the multifaceted role of the heat shock protein TRAP1

Matassa

Arzeni

Landriscina

et al. 2014

Endoplasmic Reticulum Stress in Diseases

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Abbreviations TRAPis involved in ER stress protection of cancer cellsTRAP1 (Tumour Necrosis Factor Receptor-Associated Protein 1) is a molecular chaperone, member of the HSP90 family, that contributes to the overall survival of cancer cells and is up-regulated in most tumour types (reviewed in 1). A large body of literature demonstrates that TRAP1 is part of a pro-survival signalling pathway aimed at evading the toxic effects of oxidants and anticancer drugs and plays a role in protecting mitochondria against apoptotic stimuli (reviewed in 2). However, whether its roles are uniformly oncogenic or not is now a matter of intense debate. Interestingly, Yoshida and colleagues [3] propose a more subtle reading of TRAP1 roles in the regulation of cellular metabolism and its impact on tumorigenesis. In fact, an inverse correlation between TRAP1 expression and tumor stage in cervical, bladder, and clear cell renal cell carcinoma was demonstrated. These conflicting observations on TRAP1 "behaviour" in different biological contexts is strictly related to a specific molecular complex/integrated network in which TRAP1 represents one of the focal nodes.Abstract: TRAP1 is an HSP90 chaperone, upregulated in human cancers and involved in organelles' homeostasis and tumor cell metabolism. Indeed, TRAP1 is a key regulator of adaptive responses used by highly proliferative tumors to face the metabolic stress induced by increased demand of protein synthesis and hostile environments. Besides well-characterized roles in prevention of mitochondrial permeability transition pore opening and in regulating mitochondrial respiration, TRAP1 is involved in novel regulatory mechanisms: i) the attenuation of global protein synthesis, ii) the co-translational regulation of protein synthesis and ubiquitination of specific client proteins, and iii) the protection from Endoplasmic Reticulum stress. This provides a crucial role to TRAP1 in maintaining cellular homeostasis through protein quality control, by avoiding the accumulation of damaged or misfolded proteins and, likely, facilitating the synthesis of selective cancer-related proteins. Herein, we summarize how these regulatory mechanisms are part of an integrated network, which enables cancer cells to modulate their metabolism and to face, at the same time, oxidative and metabolic stress, oxygen and nutrient deprivation, increased demand of energy production and macromolecule biosynthesis. The possibility to undertake a new strategy to disrupt such networks of integrated control in cancer cells holds great promise for treatment of human malignancies.

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The eIF3 Interactome Reveals the Translasome, a Supercomplex Linking Protein Synthesis and Degradation Machineries

Cited by 123 publications

References 75 publications

Degradation of Newly Synthesized Polypeptides by Ribosome-Associated RACK1/c-Jun N-Terminal Kinase/Eukaryotic Elongation Factor 1A2 Complex

Degradation of Newly Synthesized Polypeptides by Ribosome-Associated RACK1/c-Jun N-Terminal Kinase/Eukaryotic Elongation Factor 1A2 Complex

Expression of Truncated Eukaryotic Initiation Factor 3e (eIF3e) Resulting from Integration of Mouse Mammary Tumor Virus (MMTV) Causes a Shift from Cap-dependent to Cap-independent Translation

ER stress protection in cancer cells: the multifaceted role of the heat shock protein TRAP1

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