Reactome | ATF6B (ATF6-beta) activates chaperones

ATF6B (ATF6-beta) activates chaperones

Stable Identifier

R-HSA-8874177

DOI

10.3180/R-HSA-8874177.2

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Like its homolog ATF6 (reviewed in Fox and Andrew 2015), ATF6B is activated by cleavage in response to endoplasmic reticulum (ER) stress (Haze et al. 2001). In unstressed cells, ATF6B spans the ER membrane where its lumenal domain probably forms a complex with HSPA5 (BiP, GRP78). During ER stress, HSPA5 dissociates from ATF6B, exposing Golgi localization signals in the lumenal domain of ATF6B and causing ATF6B to traffic to the Golgi membrane. The Golgi-resident proteases MBTPS1 (S1P) and MBTPS2 (S2P) cleave ATF6B and release the cytoplasmic (N-terminal) domain, which contains a transcription activation domain, a bZIP dimerization domain, and a nuclear localization signal (Haze et al. 2001). N-glycosylation in the lumenal domain of ATF6B is required for cleavage (Guan et al. 2009). The cytoplasmic fragment transits to the nucleus where it acts as a weak transcription activator (Haze et al. 2001). By forming heterodimers with the strong activator ATF6, ATF6B may act as an inhibitory modulator of ATF6 (Thuerauf et al. 2004, Thuerauf et al. 2007). Deletion of the ER (C-terminal) domain of ATF6B in HEK293 cells causes increased production of membrane proteins, possibly due to constitutive transit of the N-terminal domain of ATF6B to the nucleus and activation of genes (Choi et al. 2025).

Literature References

PubMed ID	Title	Journal	Year
14973138	Opposing roles for ATF6alpha and ATF6beta in endoplasmic reticulum stress response gene induction Thuerauf, DJ, Morrison, L, Glembotski, CC	J Biol Chem	2004
19693772	N-glycosylation of ATF6beta is essential for its proteolytic cleavage and transcriptional repressor function to ATF6alpha Guan, D, Wang, H, Li, VE, Xu, Y, Yang, M, Shen, Z	J. Cell. Biochem.	2009
17522056	Effects of the isoform-specific characteristics of ATF6 alpha and ATF6 beta on endoplasmic reticulum stress response gene expression and cell viability Thuerauf, DJ, Marcinko, M, Belmont, PJ, Glembotski, CC	J. Biol. Chem.	2007
11256944	Identification of the G13 (cAMP-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response Haze, K, Okada, T, Yoshida, H, Yanagi, H, Yura, T, Negishi, M, Mori, K	Biochem. J.	2001
11158310	Endoplasmic reticulum stress-induced formation of transcription factor complex ERSF including NF-Y (CBF) and activating transcription factors 6alpha and 6beta that activates the mammalian unfolded protein response Yoshida, H, Okada, T, Haze, K, Yanagi, H, Yura, T, Negishi, M, Mori, K	Mol. Cell. Biol.	2001
40281769	CRISPR-Cas9-Mediated ATF6B Gene Editing Enhances Membrane Protein Production in HEK293T Cells Choi, HJ, Kim, BR, Kim, OH, Kim, SJ	Bioengineering (Basel)	2025
25821458	Transcriptional regulation of secretory capacity by bZip transcription factors Fox, RM, Andrew, DJ	Front Biol (Beijing)	2015