| Aspect | Key points | Evidence (cite IDs) |
|---|---|---|
| Gene/protein identity | **EIF2B4** encodes the human **translation initiation factor eIF2B subunit delta (eIF2Bδ)**, corresponding to **UniProt Q9UI10**; it is a noncatalytic/regulatory component of the eIF2B complex in **Homo sapiens**. | (pqac-00000000, pqac-00000002) |
| Role in eIF2B complex | eIF2B is a **heterodecamer** with two copies each of α, β, γ, δ, and ε. **EIF2B4/eIF2Bδ** belongs to the **regulatory subunits (α/β/δ)**, contributes to **holocomplex assembly**, and participates in the **β/δ core** that supports formation of the active complex. | (pqac-00000001, pqac-00000002, pqac-00000003) |
| Structural/assembly role | Experimental MS, pulldown, and SEC studies support a structural role for δ in **decamer assembly** and inter-subcomplex organization; βδ-containing assemblies are lower-activity intermediates relative to the full holoenzyme. | (pqac-00000002, pqac-00000004, pqac-00000007) |
| Biochemical function of the complex | The **eIF2B complex** is the **guanine nucleotide exchange factor (GEF)** for **eIF2**, catalyzing **GDP→GTP exchange** to regenerate active eIF2-GTP for ternary complex formation and translation initiation. Catalytic activity resides mainly in **γ/ε**, while δ enhances full activity through regulation and assembly. | (pqac-00000001, pqac-00000009, pqac-00000011, pqac-00000016) |
| ISR inhibition mechanism | During stress, **eIF2α Ser51 phosphorylation** converts eIF2 into an inhibitor of eIF2B. Structural/mechanistic summaries place **phospho-eIF2α** at an interface **between eIF2B1 (α) and eIF2B4 (δ)**, which **blocks productive engagement of eIF2γ with catalytic eIF2Bε**, suppressing nucleotide exchange and global translation. | (pqac-00000003, pqac-00000011, pqac-00000014, pqac-00000016) |
| Subcellular localization | eIF2B localizes in the **cytoplasm** in discrete **eIF2B bodies**, which are sites of GEF activity. In mammalian cells, **small bodies** are enriched for catalytic subunits, whereas **large bodies** more often contain all subunits and are consistent with decameric complexes. | (pqac-00000005, pqac-00000011, pqac-00000012, pqac-00000015, pqac-00000030) |
| eIF2Bδ inclusion in bodies | Baseline eIF2Bδ inclusion is **cell-type specific**. Reported co-localization of δ with **small bodies**: **SH-SY5Y 20.83%**, **U373 10.63%**, **MO3.13 9.03%**; with **large bodies**: **SH-SY5Y 62.39%**, **U373 67.48%**, **MO3.13 65.00%**. Acute ER stress redistributes δ toward small bodies. | (pqac-00000005, pqac-00000030) |
| Isoforms | eIF2Bδ has at least **long and short alternatively spliced isoforms**. The **long isoform** is associated with **attenuated ISR signaling** and **impaired binding to phospho-eIF2α**, whereas the **short isoform** preserves stress-induced translational inhibition and is associated with stronger ISR marker induction. Complex integrity is retained. | (pqac-00000006, pqac-00000010) |
| Pathway context | EIF2B4 functions in the **translation initiation pathway** and the **integrated stress response (ISR)**, where changes in eIF2B activity tune global protein synthesis and selective translation of stress-responsive mRNAs such as **ATF4**. | (pqac-00000009, pqac-00000011, pqac-00000016) |
| Disease link | Pathogenic **EIF2B4** variants are linked to **vanishing white matter disease (VWM/CACH)** and **ovarioleukodystrophy**. Open Targets lists associations with **leukoencephalopathy with vanishing white matter**, **CACH syndrome**, and **ovarioleukodystrophy**. | (pqac-00000000, pqac-00000017, pqac-00000018) |
| Recent disease statistics relevant to EIF2B4 | A 2024 systematic review of EIF2B-related **ovarioleukodystrophy** compiled **20 cases worldwide**, with **median onset 19 years**; ovarian presentations included **premature ovarian failure (60%)**, **secondary amenorrhea (15%)**, **primary amenorrhea (15%)**, and **ovarian dysgenesis (5%)**. **EIF2B4 and EIF2B5** were highlighted among the more frequently implicated genes in this phenotype. | (pqac-00000017, pqac-00000018, pqac-00000019) |


*Table: This table summarizes the verified identity, molecular function, ISR mechanism, localization, isoform behavior, and disease relevance of human EIF2B4/eIF2Bδ. It is designed as a compact evidence map for functional annotation with direct context-ID citations.*