EIF2AK4

This gene encodes a member of a family of kinases that phosphorylate the alpha subunit of eukaryotic translation initiation factor-2 (EIF2), resulting in the downregulaton of protein synthesis. The encoded protein responds to amino acid deprivation by binding uncharged transfer RNAs. It may also be activated by glucose deprivation and viral infection. Mutations in this gene have been found in individuals suffering from autosomal recessive pulmonary venoocclusive-disease-2.

Full Name

EUKARYOTIC TRANSLATION INITIATION FACTOR 2 ALPHA KINASE 4

Research Area

Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to low amino acid availability (PubMed:25329545).

Plays a role as an activator of the integrated stress response (ISR) required for adaptation to amino acid starvation (By similarity).

EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, and thus to a reduced overall utilization of amino acids, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion (By similarity).

Binds uncharged tRNAs (By similarity).

Involved in cell cycle arrest by promoting cyclin D1 mRNA translation repression after the unfolded protein response pathway (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in response to amino acid deprivation (PubMed:26102367).

Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory (By similarity).

Plays a role in neurite outgrowth inhibition (By similarity).

Plays a proapoptotic role in response to glucose deprivation (By similarity).

Promotes global cellular protein synthesis repression in response to UV irradiation independently of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAPK signaling pathways (By similarity).

Plays a role in the antiviral response against alphavirus infection; impairs early viral mRNA translation of the incoming genomic virus RNA, thus preventing alphavirus replication (By similarity).

(Microbial infection) Plays a role in modulating the adaptive immune response to yellow fever virus infection; promotes dendritic cells to initiate autophagy and antigene presentation to both CD4+ and CD8+ T-cells under amino acid starvation (PubMed:24310610).

Biological Process

Adaptive immune response Source: UniProtKB-KW
Cell cycle Source: UniProtKB-KW
Cellular response to amino acid starvation Source: UniProtKB
Cellular response to cold Source: UniProtKB
Cellular response to leucine starvation Source: UniProtKB
Cellular response to UV Source: UniProtKB
Defense response to virus Source: UniProtKB-KW
DNA damage checkpoint signaling Source: InterPro
EiF2alpha phosphorylation in response to endoplasmic reticulum stress Source: UniProtKB
GCN2-mediated signaling Source: UniProtKB
Induction by virus of host autophagy Source: UniProtKB
Learning Source: UniProtKB
Long-term memory Source: UniProtKB
Negative regulation by host of viral genome replication Source: UniProtKB
Negative regulation of CREB transcription factor activity Source: UniProtKB
Negative regulation of neuron differentiation Source: UniProtKB
Negative regulation of translational initiation Source: UniProtKB
Negative regulation of translational initiation in response to stress Source: UniProtKB
Neuron projection extension Source: UniProtKB
Positive regulation of adaptive immune response Source: UniProtKB
Positive regulation of defense response to virus by host Source: UniProtKB
Positive regulation of long-term synaptic potentiation Source: UniProtKB
Positive regulation of protein phosphorylation Source: Ensembl
Positive regulation of translational initiation in response to starvation Source: UniProtKB
Protein autophosphorylation Source: UniProtKB
Protein phosphorylation Source: UniProtKB
Regulation of feeding behavior Source: UniProtKB
Regulation of translational initiation Source: UniProtKB
Regulation of translational initiation by eIF2 alpha phosphorylation Source: UniProtKB
T cell activation involved in immune response Source: UniProtKB
Viral translation Source: UniProtKB

Cellular Location

Cytoplasm

Involvement in disease

Pulmonary venoocclusive disease 2, autosomal recessive (PVOD2):
A disease characterized by widespread fibrous obstruction and intimal thickening of septal veins and preseptal venules, a low diffusing capacity for carbon monoxide, occult alveolar hemorrhage, and nodular ground-glass opacities, septal lines and lymph node enlargement showed by high-resolution computed tomography of the chest. It is frequently associated with pulmonary capillary dilatation and proliferation, and is a rare and devastating cause of pulmonary hypertension.

PTM

Autophosphorylated; autophosphorylation on Thr-899 is increased upon amino acid starvation and in UV irradiation cells and inhibited in presence of IMPACT.