# EIF4E2 / 4EHP (O60573) research notes

eIF4E homologous protein (4EHP). Class II eIF4E-family cap-binding protein.

## Core function: non-canonical cap binding that REPRESSES initiation
4EHP binds the m7G cap but cannot recruit eIF4G, so it competes with eIF4E and blocks
eIF4F assembly, repressing cap-dependent translation initiation.

- UniProt FUNCTION: "Recognizes and binds the 7-methylguanosine-containing mRNA cap during
  an early step in the initiation. Acts as a repressor of translation initiation ... In
  contrast to EIF4E, it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3), suggesting that
  it acts by competing with EIF4E and block assembly of eIF4F at the cap"
- Cap binding structurally confirmed [PMID:17368478 "Structures of the human eIF4E homologous
  protein, h4EHP, in its m7GTP-bound and unliganded forms."]
- Original cloning [PMID:9582349 "Cloning and characterization of 4EHP, a novel mammalian
  eIF4E-related cap-binding protein."]

## 4EHP-GIGYF2 module + RQC
UniProt: "Component of the 4EHP-GYF2 complex ... In association with GIGYF2, assists
ribosome-associated quality control (RQC) by sequestering the mRNA cap, blocking ribosome
initiation and decreasing the translational load on problematic messages."
[PMID:32726578 RQC; PMID:22751931 development].

## miRNA silencing via CCR4-NOT / P-body
[PMID:28487484 "Here we show that the cap-binding eIF4E-homologous protein 4EHP is an integral
component of the miRNA-mediated silencing machinery. We demonstrate that the cap-binding
activity of 4EHP contributes to the translational silencing by miRNAs through the CCR4-NOT
complex."] Also controls IFNB1 via miR-34a negative feedback. P-body localization.

## SARS-CoV-2
nsp2-GIGYF2 enhances GIGYF2-EIF4E2 binding to repress IFNB1 translation [PMID:35878012].

## Ubiquitylation by HHARI
[PMID:14623119 "Human homologue of ariadne promotes the ubiquitylation of translation
initiation factor 4E homologous protein, 4EHP."] -> GO:0031625 ubiquitin protein ligase
binding (HHARI/ARIH1). Real interaction.

## IMPORTANT annotation caveats
- IBA/IEA "translation initiation factor activity" (GO:0003743) and "part of eIF4F complex"
  (GO:0016281) and "translational initiation" (GO:0006413) are MISLEADING: 4EHP does NOT
  promote initiation and is NOT a functional eIF4F component (cannot bind eIF4G). It is a
  REPRESSOR. These are phylogenetic/electronic transfers from the eIF4E family and should be
  MARK_AS_OVER_ANNOTATED or MODIFY toward repressor terms.
- A hypoxia-specific report (Uniacke) proposes 4EHP can support cap-dependent translation of
  specific mRNAs under hypoxia, but the dominant, well-established function is repression.
- Many protein binding IPI = HT interactome -> KEEP_AS_NON_CORE / MARK_AS_OVER_ANNOTATED.
- GO:1990261 pre-mRNA catabolic process (NAS ComplexPortal) -> MODIFY (mature mRNA decay).

## Core MF/BP for review
- MF: GO:0000340 RNA 7-methylguanosine cap binding (ACCEPT); GO:0045182 translation regulator /
  repressor; cap binding underlies repression.
- BP: GO:0045947 negative regulation of translational initiation (ACCEPT, core);
  GO:0072344 rescue of stalled cytosolic ribosome (ACCEPT, RQC); GO:0035278 miRNA silencing.