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FLASH GENE
Symbol ATF6 contributors: mct/npt - updated : 09-12-2017
HGNC name activating transcription factor 6
HGNC id 791
Corresponding disease
ACHM7 achromatopsia 7
Location 1q23.3      Physical location : 161.736.083 - 161.928.851
Synonym name
  • cyclic AMP-dependent transcription factor ATF-6 alpha
    • Synonym symbol(s) ATF6A, DKFZp686P2194, FLJ21663
    DNA
    TYPE functioning gene
    STRUCTURE 192.77 kb     16 Exon(s)
    Genomic sequence alignment details
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site
    text structure
  • promoter having a RUNX2-binding motif
    • MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    16 - 2488 74.5 670 - 1999 10564271
    - - - - - - 2007 17522056
  • N-terminal fragments have conserved DNA-binding domains and divergent transcriptional activation domains
  • cleaved during the ER stress response
  • sensor of the endoplasmic reticulum stress response that regulates the expression of genes involved in the unfolded protein response
    • - - - - - - 2007 17522056
  • N-terminal fragments have conserved DNA-binding domains and divergent transcriptional activation domains
  • cleaved during the ER stress response
  • endogenous inhibitor of ATF6 alpha
    • - - - 90 - - 2004 14699159
  • p90ATF6 activation requires transit from the ER to the Golgi, where it is cleaved by the S1P/S2P protease system to generate a nuclear form p60ATF6 that acts as a transcriptional activator
  • glycosylation status of p90ATF6 can serve as a sensor for ER homeostasis, resulting in ATF6 activation to trigger the unfolded protein response
    • - - - 60 - - 2004 14699159
    p90ATF6 activation requires transit from the ER to the Golgi, where it is cleaved by the S1P/S2P protease system to generate a nuclear form p60ATF6 that acts as a transcriptional activator
    EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveesophagus   highly
     mouthtongue  highly
    Reproductivefemale systemuteruscervix highly
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal domain facing the cytosol containing DNA-binding and a transcription-activating domain
  • three evolutionarily conserved N-linked glycosylation sites within its carboxyl luminal domain
  • a basic leucine zipper (bZIP) in the N terminal half
  • a hydrophobic stretch in the middle of the molecule
  • a luminal domain alone sufficient for sensing ER stress and subsequent transportation to the Golgi apparatus
  • C terminus in the ER lumen
    • conjugated GlycoP
    HOMOLOGY
    Homologene
    FAMILY
  • bZIP family
  • ATF/CREB family of transcription factors
    • CATEGORY chaperone/stress
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,nucleus,nucleoplasm
    intracellular,nuclear envelope
    text
  • moving to Golgi when it is cut by serine proteases, releasing p50ATF6 that translocates into the nucleus
  • in response to ER stress, ATF6 is transported to the Golgi apparatus, processed by the S1P and S2P proteases
  • constitutively synthesized as a type II transmembrane protein embedded in the endoplasmic reticulum (ER)
    • basic FUNCTION
  • transcription factor that activates the transcription of ER molecules
  • key transcriptional activator of the unfolded protein response (UPR), which allows mammalian cells to maintain cellular homeostasis when they are subjected to a variety of environmental and physiological stresses that target the endoplasmic reticulum
  • potent activator of ER stress-response genes (ERSRG), and was required for maximal ERSRG induction
  • ATF6 and ATF6B, are cleaved during the ER stress response (ERSR)
  • relative levels of ATF6 and ATF6B, may contribute to regulating the strength and duration of ATF6-dependent ERSR gene induction and cell viability
  • ER membrane-anchored transcription factor, transported to the Golgi apparatus and cleaved by site-1 protease (S1P) to activate the unfolded protein response, in response to ER stress
  • antagonizes SREBF2 to regulate the homeostasis of lipid and glucose
  • transcription factor specialized in the regulation of ER quality control proteins
  • ER-membrane-bound transcription factor that is activated by protein misfolding in the ER and functions as a critical regulator of ER quality control proteins
  • ATF6-mediated transcriptional induction of ER-localized molecular chaperones and folding enzymes together with components of ER-associated degradation leads to the maintenance of ER homeostasis
  • controls the levels of ER chaperones and ERAD component in dopaminergic neurons-containing brain regions
  • functions as a transcriptional factor of osteogenic BGLAP gene expression
  • ER stress transducer ATF6 might be a novel positive mediator of BMP2-induced osteoblast differentiation and extracellular matrix mineralization
  • in response to ER stress, ATF6 translocates to the nucleus and activates transcription of ER stress response genes upon binding sequence specifically to ER stress response enhancer elements in their promoters
  • functions as a master regulator of endoplasmic reticulum (ER) stress response genes
  • single prolonged stress induces ATF6-dependent endoplasmic reticulum stress and the apoptotic process in medial frontal cortex neurons
  • endoplasmic reticulum-resident transcription factor
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
  • the EIF2AK3 pathway facilitates both the synthesis of ATF6 and trafficking of ATF6 from the ER to the Golgi for intramembrane proteolysis and activation of ATF6
  • BMP2-RUNX2-ATF6 signal pathway positively regulates osteoblast differentiation and extracellular matrix mineralization
    • a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • trimeric nuclear factor Y (NFY) and with YY1
  • serum response factor SRF for binding to the SRE element of FOS
  • activating transcription of GRP78 (HJAP5) (kept inactive by binding with GRP78 in the ER lumen)
  • interacting with VAPA an VAPB
  • bZIP domain of ATF6, which shares high sequence similarity with ATF6B, interact with NS4B in yeast although the interaction was weaker than that between NS4B and ATF6B
  • interacting with ATF6B (unglycosylated ATF6B may directly facilitate the expression of ER stress response (ERSR) genes by losing its repressor function to ATF6)
  • MAPK14 can regulate ATF6 function via phosphorylation, suggesting the possibility that oxidative stress and ER stress intersect at the level of MAPK14 and ATF6
  • interaction between phosphorylated MAPK14 and cleaved N-terminal ATF6 could results in a protective effect against the vicious cycle of oxidative stress-ER stress by induction of ER chaperones and ERAD components
  • BMP2 induces osteoblast differentiation through RUNX2-dependent ATF6 expression, which directly regulates BGLAP transcription
  • RUNX2 is essential to the BMP2 induction of ATF6 expression but is not needed to determine the subcellular localization of ATF6
  • ATF6 increases BGLAP transcription via directly binding to BGLAP promoter
  • BMP2 is known to activate unfolded protein response signaling molecules, including XBP1 and ATF6
  • PARM1 may regulate EIF2AK3, ATF6, and DDIT3 expression through BMP2 expression
  • RRBP1 may involve in the regulation of mRNA stability of UPR components including ATF6 and HSPA5 (PMId: 23318453)
  • recruits Mediator to activate endoplasmic reticulum stress response genes (PMISD: 23864652)
  • ERN1, ATF6, and EIF2AK3 signaling pathways, collectively called the unfolded protein response (UPR), regulate the functions of endoplasmic reticulum, responsible for accurate folding of membrane proteins such as RHO
  • ATF6 is sufficient to induce the LMF1 promoter in the absence of ER stress, and this effect is mediated by the TM-responsive cis-regulatory element
  • in association with the transcription factor CEBPB, regulates IFNG-induced expression of DAPK1
  • role of ORMDL3 in fine-tuning B cell development and survival, besides highlighting a potential mechanism by which ORMDL3 regulates autophagy via ATF6
  • among UPR-related transcription factors, XBP1 upregulated ACTN2, whereas XBP1, ATF4 and ATF6 downregulated ACTN3 promoter activity
    • cell & other
    REGULATION
    activated by and cleaved by MBTPS1 and MBTPS2 in the ER stress response, when unfolded proteins accumulate in the endoplasmic reticulum (UPR:unfolded protein response)
    selective activation of the transcription factor ATF6 mediates endoplasmic reticulum proliferation triggered by a membrane protein
    activated in response to ER stress
    inhibited by WFS1 (WFS1 negatively regulates ATF6 a key transcription factor involved in ER stress signaling, through the ubiquitin-proteasome pathway)
    repressed by NUCB1
    Other ATF6 and ATF6B, are cleaved in response to ER stress, which can be induced by tunicamycin
    ASSOCIATED DISORDERS
    corresponding disease(s) ACHM7
    Susceptibility to type 2 diabetes in Pima Indians
    Variant & Polymorphism other polymorphisms significantly associated to type 2 diabetes
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerativeParkinson/dementia Parkinsonism
    ATF6α-mediated induction of ER chaperones and ERAD components via p38MAPK pathway may provide a therapeutic target for Parkinson disease and other neurodegenerative diseases associated with protein misfolding
    neurosensorialvisualretina
    activation of ERN1 or ATF6 can selectively remove aggregated or mutant RHO from the cells and may be useful in treating RP associated with rhodopsin protein misfolding
    ANIMAL & CELL MODELS