Disease relevance of ATF6

• This portion of ATF6 was found to be homologous to the herpes simplex viral protein, VP16 [1].
• The GC-rich nonanucleotide (N(9)) sequence, which forms the ER stress response binding factor (ERSF) complex binds TFII-I and ATF6; however, we have now shown that in Panc-1 pancreatic cancer cells, this complex also binds Sp1, Sp3, and Sp4 proteins [2].
• CONCLUSION: ATF6 and DUSP12 seem to be the most likely candidate target genes for the 1q23 amplification in sarcomas [3].
• AR112Q toxicity was significantly increased by a dominant negative ATF6 mutant and significantly decreased by a constitutively active ATF6 mutant, indicating that ATF6 promoted cell survival [4].
• Other substrates include the stress response factor activating transcription factor-6, the brain-derived neurotrophic factor, and the surface glycoproteins of highly infectious viruses belonging to the family of Arenaviridae [5].

High impact information on ATF6

• Valproate, one of three mood stabilizers, rescued the impaired response by inducing ATF6, the gene upstream of XBP1 [6].
• ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively [7].
• Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress [7].
• ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response [7].
• Here, we report that glucose deprivation activated ATF6 but suppressed the SREBP2-regulated transcription [8].

Biological context of ATF6

• Our results provide a novel mechanism by which ATF6 antagonizes SREBP2 to regulate the homeostasis of lipid and glucose [8].
• Deletion analysis of the various functional domains of ATF6 indicated that the interaction was through its leucine-zipper domain [8].
• ATF6 modulates SREBP2-mediated lipogenesis [8].
• Of primary importance is a functional NF-Y complex and a high-affinity NF-Y binding site that confers selectivity among different ERSEs for ATF6 inducibility [9].
• We propose that phosphorylation of ATF6 is a novel mechanism for augmenting its potential as a transcription activator [10].

Anatomical context of ATF6

• Here we report that eukaryotic cells express another bZIP protein closely related to ATF6 in both structure and function [11].
• Transcriptional activation dependent on an ATF6-XBP-1 binding site was detected by transient expression in MCF-7, C33A, and a transformed epithelial cell line (HaCaT); induction of the GADD153 (CHOP) promoter was also confirmed by transient expression [12].
• An ATF6-VP16 chimera activated expression of an SRE reporter gene in HeLa cells, suggesting that ATF6 can interact with endogenous SRF [13].
• These results indicate that the ER stress pathway involving ATF6 and CHOP plays a key role in NO-mediated apoptosis in macrophages [14].
• A study by, in this issue of Developmental Cell shows that transport to the Golgi complex and subsequent proteolytic activation of the stress-regulated transcription factor ATF6 is initiated by the dissociation of the ER chaperone BiP from ATF6 [15].

Associations of ATF6 with chemical compounds

• In addition, we have re-localized S1P and S2P to the ER with brefeldin A and find that the sequential cleavage of ATF6 is reconstituted in the ER [16].
• This protein encoded by the G13 (cAMP response element binding protein-related protein) gene is constitutively synthesized as a type II transmembrane glycoprotein anchored in the ER membrane and processed into a soluble form upon ER stress as occurs with ATF6 [11].
• We found that this luminal domain is required for the translocation of ATF6 to the Golgi and its subsequent cleavage, and we have mapped regions required for these properties [17].
• Regulated intramembrane proteolysis of the factors SREBP and ATF6 represents a central control mechanism in sterol homeostasis and stress response within the endoplasmic reticulum [18].
• Disulfide-bonded ATF6 is reduced upon treatment of cells with not only the reducing reagent dithiothreitol but also the glycosylation inhibitor tunicamycin, and the extent of reduction correlates with that of activation [19].

Physical interactions of ATF6

• In addition, we showed that YY1 interacts with ATF6 and in Tg-treated cells can enhance ATF6 activity [9].
• A serine protease inhibitor prevents endoplasmic reticulum stress-induced cleavage but not transport of the membrane-bound transcription factor ATF6 [20].
• These methods were used to investigate several key steps of ATF6 activation in the ER stress response including binding and dissociation of BiP to ATF6, translocation from the ER to the Golgi and cleavage in the Golgi [21].
• Upon ER stress ATF6 is transported to the Golgi apparatus where it is cleaved to release its cytoplasmic domain [22].

Regulatory relationships of ATF6

• XBP1 is also induced by activated ATF6 [23].
• In contrast, mutant ATF6 representing the cytoplasmic region translocates into the nucleus and activates transcription of the endogenous GRP78/BiP gene [24].
• DUSP12 was expressed significantly higher than ATF6 in a subset of the tumours [3].
• In vitro DNA binding experiments showed that recombinant N-ATF6 beta inhibited the binding of recombinant N-ATF6 alpha to an ERSR element from the GRP78 promoter [25].

Other interactions of ATF6

• Grp78 is a molecular chaperone involved in the unfolded protein response, the expression of which can be regulated by the transcription factors ATF6 and XBP1 [26].
• The proteolytic processing of ATF6 and the G13 gene product is accompanied by their relocation from the ER to the nucleus; their basic regions seem to function as a nuclear localization signal [11].
• We show that YY1 is an essential coactivator of ATF6 and uncover their specific interactive domains [27].
• Higher accumulation of the grp78 product in the cytoplasm, concomitantly with marked nuclear localization of the activated ATF6 product (p50ATF6), was observed in moderately to poorly differentiated HCC tissues [26].
• We demonstrate that HCV NS4B could induce activating transcription factor (ATF6) and inositol-requiring enzyme 1 (IRE1), to favor the HCV subreplicon and HCV viral replication [28].

Analytical, diagnostic and therapeutic context of ATF6

• This new form of ATF6 was recovered as soluble nuclear protein by biochemical fractionation, correlating with enhanced nuclear localization of ATF6 as revealed by immunofluorescence [9].
• Toward understanding the underlying mechanisms of these unique phenomena, we performed chromatin immunoprecipitation analyses, revealing that YY1 only occupies the Grp78 promoter upon ER stress and is mediated in part by the nuclear form of ATF6 [27].
• METHODS: Expression of grp78, ATF6 and XBP1 was examined by Northern blot, RT-PCR, immunoblot and immunohistochemical analyses [26].
• The mechanisms by which mutant PS1 affects the ER stress response are attributed to the inhibited activation of ER stress transducers such as IRE1, PERK and ATF6 [29].
• Although PERK and IRE1 are activated in the initial hours of reperfusion, total PERK decreases, ATF6 is not activated, and there is delayed appearance of UPR-induced mRNAs [30].

References