ATF4
Description
The ATF4 (activating transcription factor 4) is a protein-coding gene located on chromosome 22.
Activating transcription factor 4 (tax-responsive enhancer element B67), also known as ATF4, is a protein that in humans is encoded by the ATF4 gene.
== Function == This gene encodes a transcription factor that was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was also isolated and characterized as the cAMP-response element binding protein 2 (CREB-2). The protein encoded by this gene belongs to a family of DNA-binding proteins that includes the AP-1 family of transcription factors, cAMP-response element binding proteins (CREBs) and CREB-like proteins. These transcription factors share a leucine zipper region that is involved in protein–protein interactions, located C-terminal to a stretch of basic amino acids that functions as a DNA-binding domain. Two alternative transcripts encoding the same protein have been described. Two pseudogenes are located on the X chromosome at q28 in a region containing a large inverted duplication. ATF4 transcription factor is also known to play role in osteoblast differentiation along with RUNX2 and osterix. Terminal osteoblast differentiation, represented by matrix mineralization, is significantly inhibited by the inactivation of JNK. JNK inactivation downregulates expression of ATF-4 and, subsequently, matrix mineralization. IMPACT protein regulates ATF4 in C. elegans to promote lifespan.
ATF4 is a transcription factor that binds to the cAMP response element (CRE) and plays two key roles: regulating metabolic and redox processes under normal conditions and acting as a master transcription factor during the integrated stress response (ISR). It binds to asymmetric CREs as a heterodimer and to palindromic CREs as a homodimer. ATF4 is a core effector of the ISR, essential for adapting to various stresses like endoplasmic reticulum (ER) stress, amino acid starvation, mitochondrial stress, and oxidative stress. During ISR, ATF4 translation is triggered by EIF2S1/eIF-2-alpha phosphorylation, leading to the production of ATF4 that activates stress-responsive genes, promoting cell recovery. ATF4 promotes the transcription of genes involved in amino acid sufficiency and resistance to oxidative stress to protect cells against metabolic consequences of ER oxidation. It activates the transcription of NLRP1 in response to ER stress, possibly in collaboration with other factors. ATF4 also activates the transcription of asparagine synthetase (ASNS) in response to amino acid deprivation or ER stress. However, when associated with DDIT3/CHOP, the transcriptional activation of ASNS is inhibited in response to amino acid deprivation. Together with DDIT3/CHOP, ATF4 mediates programmed cell death by promoting the expression of genes involved in cellular amino acid metabolic processes, mRNA translation, and the terminal unfolded protein response (terminal UPR), which triggers programmed cell death when ER stress persists. Alongside DDIT3/CHOP, ATF4 activates the transcription of the IRS-regulator TRIB3 and promotes ER stress-induced neuronal cell death by regulating the expression of BBC3/PUMA in response to ER stress. ATF4 might cooperate with the UPR transcriptional regulator QRICH1 to regulate ER protein homeostasis, which is crucial for cell viability under ER stress. In the absence of stress, ATF4 translation is low and it is needed for normal metabolic processes such as embryonic lens formation, fetal liver hematopoiesis, bone development, and synaptic plasticity. ATF4 acts as a regulator of osteoblast differentiation in response to phosphorylation by RPS6KA3/RSK2. Phosphorylation in osteoblasts enhances ATF4's transactivation activity, promoting the expression of osteoblast-specific genes and post-transcriptionally regulating the synthesis of Type I collagen, the main component of the bone matrix. ATF4 collaborates with FOXO1 in osteoblasts to regulate glucose homeostasis by suppressing beta-cell production and decreasing insulin production. ATF4 activates the transcription of SIRT4. It regulates the circadian expression of the core clock component PER2 and the serotonin transporter SLC6A4. ATF4 binds in a circadian time-dependent manner to the cAMP response elements (CRE) in the SLC6A4 and PER2 promoters and periodically activates the transcription of these genes. ATF4 mainly functions as a transcriptional activator in cellular stress adaptation but can also act as a transcriptional repressor. It regulates synaptic plasticity by repressing transcription, thereby inhibiting the induction and maintenance of long-term memory. ATF4 regulates synaptic functions through interactions with DISC1 in neurons. DISC1 inhibits ATF4's transcription factor activity by disrupting ATF4 dimerization and DNA-binding.
ATF4 is also known as CREB-2, CREB2, TAXREB67, TXREB.
