ATF4

cAMP response element binding protein 2

CREB2

CREB-2

tax-responsive enhancer element B67

TAXREB67

ATF4

ATF4

ATF4

ATF4

1–42

, also known as) [ 25 ], 26 ], or) [ 27 ], was originally cloned by screening with a DNA probe containing ATF-binding sites [ 28 ] and was later identified as a tax-responsive enhancer element in the LTR of HTLV-1 binding protein [ 27 ]. ATF4 has a leucine zipper region for protein interaction and a stretch of basic amino acids for DNA binding at the C-terminal, and belongs to the ATF/CREB protein family [ 26 ].mRNA is widely expressed in mammalian tissues including the brain.is controlled translationally by regulated re-initiation [ 29 30 ]. MousemRNA has two upstream open reading frames (uORFs), uORG1 and uORF2, in the 5′ noncoding region. uORF1 and uORF2 encode three and sixty amino acid residues, respectively, and uORF1 localizes upstream of uORF2 and the ATF4 coding region. Currently, a model of ATF4 translation proposes that in the presence of a high number of ternary complexes of met-tRNAi and eIF2α-GTP in non-stressed conditions, ribosomes scan and translate uORF1 and reinitiate translation of uORF2. After translation of uORF2, ribosomes dissociate from themRNA, leading to a reduction in ATF4 coding region translation. On the other hand, in cases of reduced levels of the ternary complex during stressed conditions, re-initiation of uORF2 translation is suppressed by a delay in the reacquisition of the ternary complex after translation of uORF1. Therefore, the ribosome scans and initiates translation of the ATF4 coding region [ 29 31 ]. ATF4 is degraded through the E3 ubiquitin ligase SCF (Skp1/Cullin/F-box protein) containing the β-transducin-repeat-containing protein (β-TRCP) [ 32 ], indicating that ATF4 expression is regulated by translation and post-translation. ATF4 heterodimerizes with Nrf2 to regulate heme oxygenase-1 (HO-1) expression [ 33 ]. Phosphorylation of ATF4 by protein kinase A regulates the expression of several genes such as the osteoclast differentiation factor Rankl [ 34 ]. ATF4 is phosphorylated by RSK2, the growth factor-regulated kinase whose mutation causes Coffin–Lowry syndrome that is associated with mental retardation and skeletal abnormalities [ 35 ]. ATF4 is essential for lens fiber cell differentiation [ 36 ]. These studies indicate that ATF4 is important for differentiation of bone and the lens, amino acid metabolism, and resistance to oxidative stress [ 22 ]. ATF4 also plays roles in several physiological processes such as memory [ 25 37 ]; that is, ATF4 binds CREB to control its activity [ 25 ], and expression of a dominant negative CREB2 improves spatial learning, indicating that ATF4 works as a memory-suppressor gene [ 37 ]. The ATF4 protein has been reported to be present in the axons of the brains of patients with AD. ATF4 is synthesized in the axon of primary hippocampal rat neurons exposed to amyloid-β (Aβ), which induces eIF2α phosphorylation in the axons, causing neuronal cell death [ 38 ]. Overexpression of ATF4 in the nucleus accumbens of rats showed an anxiolytic-like response. However, depression-like behavior was also observed [ 39 ]. On the other hand, knockdown of ATF4 in the mouse hippocampus resulted in an impairment of spatial memory, decreased spine and puncta of the PSD95 and AMPA receptor GluR1, indicating that ATF4 plays a key role in synapse formation and memory [ 40 ]. These studies indicated that exploration of the regulation of ATF4 expression is important for the treatment of several diseases. Recently, three mechanisms have been proposed. First, feedback inhibition by GADD34 wherein eIF2α is dephosphorylated, leading to a suppression of ATF4 expression and a recovery of protein synthesis [ 21 ]. Second, ATF6-induced p58expression, which has been identified as an inhibitor of the interferon-induced PKR, suppresses PERK activity, leading to the suppression of eIF2α phosphorylation and ATF4 expression [ 41 42 ]. Lastly, ER stress-induced ATF4 expression is suppressed by pretreatment with low doses of lipopolysaccharide (LPS), which activates toll-like receptor 4 signaling, independently of the suppression of the phosphorylation of PERK or eIF2α [ 43 ], like an ISR inhibitor (ISRIB) [ 44 ].