ATF4 belongs to the ATF/cAMP-response element-binding protein family. It is a transcriptional activator that binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters [, ]. It plays a crucial role in the adaptation to stresses by regulating the transcription of many genes [].
Transducin beta-like protein 2 (TBL2), also known as WBSCR13, has been linked to Williams-Beuren syndrome []. It contains an N-terminal transmembrane region and the C-terminal WD40 domain []. Under endoplasmic reticulum (ER) stress, TBL2 is involved in ATF4 translation through its association with the mRNA [].
Tribbles encode an evolutionarily conserved protein family that influences proliferation, motility, metabolism, and oncogenic transformation. Originally identified in Drosophila, tribbles homologues are characterised by a central serine/threonine kinase-like domain (KD) and a C-terminal binding site for E3 ubiquitin ligases. Although the KD is the defining feature of the tribbles family, these proteins are considered to be catalytically inactive because they lack conserved residues from the characteristic adenosine triphosphate binding site and catalytic core motif within the KD [].TRB-1, TRB-2 and TRB-3 are the mammalian homologues of Drosophila tribbles. This entry represents TRB-3, which binds to ATF4 and inhibits its transcriptional activation activity []. It also interacts with and regulates activation of MAP kinases [].
This entry represents eukaryotic translation initiation factor 4 gamma 1 (EIF4G1), which is a component of the eIF4F complex. The eIF4F complex is required for recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome. Mitogen-activated protein kinases control translation by post-translational modification of translation initiation factors, and eIF4G1 is a substrate for protein kinase C []. As part of the eIF4F complex, EIF4G1 mediates endoplasmic reticulum stress-induced ATF4 (a master stress-induced transcription factor) mRNA translation []. Mutations in the EIF4G1 gene cause Parkinson disease 18, which is a neurodegenerative disorder with the following symptoms: bradykinesia, resting tremor, muscular rigidity and postural instability, and loss of dopaminergic neurons from the substantia nigra []. Viral infection can lead to the shutdown of translation by cleavage of EIF4G1, for example, by HIV-1 retropepsin [], rhinovirus picornain 2A []and foot-and-mouth disease virus L-peptidase [].
