Last update 19 Sep 2024

EIF4G1

Last update 19 Sep 2024

Basic Info

Synonyms

eIF-4-gamma 1, eIF-4G 1, eIF-4G1

+ [7]

Introduction

Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome (PubMed:29987188). Exists in two complexes, either with EIF1 or with EIF4E (mutually exclusive) (PubMed:29987188). Together with EIF1, is required for leaky scanning, in particular for avoiding cap-proximal start codon (PubMed:29987188). Together with EIF4E, antagonizes the scanning promoted by EIF1-EIF4G1 and locates the start codon (through a TISU element) without scanning (PubMed:29987188). As a member of the eIF4F complex, required for endoplasmic reticulum stress-induced ATF4 mRNA translation (PubMed:29062139).

Drugs associated with EIF4G1

4EGI-1

Target

EIF4E x EIF4G1

Mechanism

EIF4E inhibitors [+1]

Active Org.

Harvard Medical School

Originator Org.

Harvard Medical School

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

FEP-633

Target

EIF4E x EIF4G1

Mechanism

EIF4E inhibitors [+1]

Active Org.

PRISM BioLab Co., Ltd.

Originator Org.

PRISM BioLab Co., Ltd.

Active Indication

Bladder Cancer

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SBI-0640756

Target

EIF4G1

Mechanism

EIF4G1 inhibitors

Active Org.-

Originator Org.

Sanford Burnham Prebys Medical Discovery Institute

Active Indication-

Inactive Indication

Melanoma

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with EIF4G1

100 Translational Medicine associated with EIF4G1

0 Patents (Medical) associated with EIF4G1

1,470

Literatures (Medical) associated with EIF4G1

01 Sep 2024·Genes to Cells

An N‐terminal and ankyrin repeat domain interactome of Shank3 identifies the protein complex with the splicing regulator Nono in mice

Article

Author: Okuzono, Sayaka ; Matsushita, Yuki ; Shinmyo, Yohei ; Sakurai, Takeshi ; Kang, Dongchon ; Han, Kihoon ; Taira, Ryoji ; Yonemoto, Kousuke ; Kato, Hiroki ; Motomura, Yoshitomo ; Akamine, Satoshi ; Fujii, Fumihiko ; Setoyama, Daiki ; Sakai, Yasunari ; Kawasaki, Hiroshi ; Ohga, Shouichi ; Kato, Takahiro A. ; Masuda, Keiji ; Nakabeppu, Yusaku ; Torisu, Hiroyuki

AbstractAn autism‐associated gene Shank3 encodes multiple splicing isoforms, Shank3a‐f. We have recently reported that Shank3a/b‐knockout mice were more susceptible to kainic acid‐induced seizures than wild‐type mice at 4 weeks of age. Little is known, however, about how the N‐terminal and ankyrin repeat domains (NT‐Ank) of Shank3a/b regulate multiple molecular signals in the developing brain. To explore the functional roles of Shank3a/b, we performed a mass spectrometry‐based proteomic search for proteins interacting with GFP‐tagged NT‐Ank. In this study, NT‐Ank was predicted to form a variety of complexes with a total of 348 proteins, in which RNA‐binding (n = 102), spliceosome (n = 22), and ribosome‐associated molecules (n = 9) were significantly enriched. Among them, an X‐linked intellectual disability‐associated protein, Nono, was identified as a NT‐Ank‐binding protein. Coimmunoprecipitation assays validated the interaction of Shank3 with Nono in the mouse brain. In agreement with these data, the thalamus of Shank3a/b‐knockout mice aberrantly expressed splicing isoforms of autism‐associated genes, Nrxn1 and Eif4G1, before and after seizures with kainic acid treatment. These data indicate that Shank3 interacts with multiple RNA‐binding proteins in the postnatal brain, thereby regulating the homeostatic expression of splicing isoforms for autism‐associated genes after birth.

01 Sep 2024·RNA

Modeling the structure and DAP5-binding site of the FGF-9 5′-UTR RNA utilized in cap-independent translation

Article

Author: Goss, Dixie J ; Whittaker, Amanda

Cap-independent or eukaryotic initiation factor (eIF) 4E-independent, translation initiation in eukaryotes requires scaffolding protein eIF4G or its homolog, death-associated protein 5 (DAP5). eIF4G associates with the 40S ribosomal subunit, recruiting the ribosome to the RNA transcript. A subset of RNA transcripts, such as fibroblast growth factor 9 (FGF-9), contain 5′ untranslated regions (5′ UTRs) that directly bind DAP5 or eIF4GI. For viral mRNA, eIF recruitment usually utilizes RNA structure, such as a pseudoknot or stem–loops, and the RNA-helicase eIF4A is required for DAP5- or 4G-mediated translation, suggesting these 5′ UTRs are structured. However, for cellular IRES-like translation, no consensus RNA structures or sequences have yet been identified for eIF binding. However, the DAP5-binding site within the FGF-9 5′ UTR is unknown. Moreover, DAP5 binds to other, dissimilar 5′ UTRs, some of which require an unpaired, accessible 5′ end to stimulate cap-independent translation. Using SHAPE-seq, we modeled the 186 nt FGF-9 5′-UTR RNA's complex secondary structure in vitro. Further, DAP5 footprinting, toeprinting, and UV cross-linking experiments identify DAP5–RNA interactions. Modeling of FGF-9 5′-UTR tertiary structure aligns DAP5-interacting nucleotides on one face of the predicted structure. We propose that RNA structure involving tertiary folding, rather than a conserved sequence or secondary structure, acts as a DAP5-binding site. DAP5 appears to contact nucleotides near the start codon. Our findings offer a new perspective in the hunt for cap-independent translational enhancers. Structural, rather than sequence-specific, eIF-binding sites may act as attractive chemotherapeutic targets or as dosage tools for mRNA-based therapies.

19 Jul 2024·Science Advances

Repression of mRNA translation initiation by GIGYF1 via disrupting the eIF3-eIF4G1 interaction

Article

Author: Guo, Shuyue ; Hesketh, Geoffrey G ; Sonenberg, Nahum ; Jafarnejad, Seyed Mehdi ; Alain, Tommy ; Gingras, Anne-Claude ; An, Yuxin ; Ladak, Reese Jalal ; Zhang, Xu ; Duchaine, Thomas ; Naeli, Parisa ; Luo, Jun ; Pistofidis, Angelos ; Choi, Jung-Hyun ; Schmeing, T Martin

Viruses can selectively repress the translation of mRNAs involved in the antiviral response. RNA viruses exploit the Grb10-interacting GYF (glycine-tyrosine-phenylalanine) proteins 2 (GIGYF2) and eukaryotic translation initiation factor 4E (eIF4E) homologous protein 4EHP to selectively repress the translation of transcripts such as Ifnb1 , which encodes the antiviral cytokine interferon-β (IFN-β). Herein, we reveal that GIGYF1, a paralog of GIGYF2, robustly represses cellular mRNA translation through a distinct 4EHP-independent mechanism. Upon recruitment to a target mRNA, GIGYF1 binds to subunits of eukaryotic translation initiation factor 3 (eIF3) at the eIF3-eIF4G1 interaction interface. This interaction disrupts the eIF3 binding to eIF4G1, resulting in transcript-specific translational repression. Depletion of GIGYF1 induces a robust immune response by derepressing IFN-β production. Our study highlights a unique mechanism of translational regulation by GIGYF1 that involves sequestering eIF3 and abrogating its binding to eIF4G1. This mechanism has profound implications for the host response to viral infections.

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EIF4G1

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