A Serine Protease Inhibitor Prevents Endoplasmic Reticulum Stress-induced Cleavage but Not Transport of the Membrane-bound Transcription Factor ATF6

Mammalian cells express several transcription factors embedded in the endoplasmic reticulum (ER) as transmembrane proteins that are activated by proteolysis, and two types of these proteins have been extensively investigated. One type comprises the sterol regulatory element-binding proteins (SREBP-1 and SREBP-2). The other type comprises the activating transcription factors 6 (ATF6α and ATF6β), which are activated in response to ER stress. It was shown previously that both SREBP and ATF6 are cleaved sequentially first by the Site-1 protease (serine protease) and then by the Site-2 protease (metalloprotease) (Ye, J., Rawson, R. B., Komuro, R., Chen, X., Dave, U. P., Prywes, R., Brown, M. S., and Goldstein, J. L. (2000) Mol. Cell 6, 1355–1364). In this study, we examined various protease inhibitors and found that 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), a serine protease inhibitor, prevented ER stress-induced cleavage of ATF6α and ATF6β, resulting in inhibition of transcriptional induction of ATF6-target genes. AEBSF also inhibited production of the mature form of SREBP-2 that was induced in response to sterol depletion, and appeared to directly prevent cleavage of ATF6α and ATF6β by inhibiting Site-1 protease. As the Site-1 protease is localized in the Golgi apparatus, both SREBP and ATF6 must relocate to the Golgi apparatus to be cleaved. We showed here that AEBSF treatment had little effect on ER stress-induced translocation of ATF6 from the ER to the Golgi apparatus, but blocked nuclear localization of ATF6. These results indicate that the transport of ATF6 from the ER to the Golgi apparatus and that from the Golgi apparatus to the nucleus are distinct steps that can be distinguished by treatment with AEBSF. Mammalian cells express several transcription factors embedded in the endoplasmic reticulum (ER) as transmembrane proteins that are activated by proteolysis, and two types of these proteins have been extensively investigated. One type comprises the sterol regulatory element-binding proteins (SREBP-1 and SREBP-2). The other type comprises the activating transcription factors 6 (ATF6α and ATF6β), which are activated in response to ER stress. It was shown previously that both SREBP and ATF6 are cleaved sequentially first by the Site-1 protease (serine protease) and then by the Site-2 protease (metalloprotease) (Ye, J., Rawson, R. B., Komuro, R., Chen, X., Dave, U. P., Prywes, R., Brown, M. S., and Goldstein, J. L. (2000) Mol. Cell 6, 1355–1364). In this study, we examined various protease inhibitors and found that 4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF), a serine protease inhibitor, prevented ER stress-induced cleavage of ATF6α and ATF6β, resulting in inhibition of transcriptional induction of ATF6-target genes. AEBSF also inhibited production of the mature form of SREBP-2 that was induced in response to sterol depletion, and appeared to directly prevent cleavage of ATF6α and ATF6β by inhibiting Site-1 protease. As the Site-1 protease is localized in the Golgi apparatus, both SREBP and ATF6 must relocate to the Golgi apparatus to be cleaved. We showed here that AEBSF treatment had little effect on ER stress-induced translocation of ATF6 from the ER to the Golgi apparatus, but blocked nuclear localization of ATF6. These results indicate that the transport of ATF6 from the ER to the Golgi apparatus and that from the Golgi apparatus to the nucleus are distinct steps that can be distinguished by treatment with AEBSF. The endoplasmic reticulum (ER) 1The abbreviations used are: ER, endoplasmic reticulum; AEBSF, 4-(2-aminoethyl)benzenesulfonylfluoride; Asn-S, asparagine synthetase; ERSE, endoplasmic reticulum stress response element; RIP, regulated intramembrane proteolysis; SREBP, sterol regulatory element-binding protein; S1P, Site-1 protease; S2P, Site-2 protease; UPR, unfolded protein response; WT, wild-type; BiP, immunoglobulin heavy chain-binding protein; ATF, activating transcription factor.1The abbreviations used are: ER, endoplasmic reticulum; AEBSF, 4-(2-aminoethyl)benzenesulfonylfluoride; Asn-S, asparagine synthetase; ERSE, endoplasmic reticulum stress response element; RIP, regulated intramembrane proteolysis; SREBP, sterol regulatory element-binding protein; S1P, Site-1 protease; S2P, Site-2 protease; UPR, unfolded protein response; WT, wild-type; BiP, immunoglobulin heavy chain-binding protein; ATF, activating transcription factor. is now known to dispatch various signals to the nucleus in response to perturbation in or around the ER, such as the depletion of intracellular sterols (1Brown M.S. Goldstein J.L. Cell. 1997; 89: 331-340Abstract Full Text Full Text PDF PubMed Scopus (2918) Google Scholar) or the accumulation of unfolded proteins in the ER (2Kaufman R.J. Genes Dev. 1999; 13: 1211-1233Crossref PubMed Scopus (1912) Google Scholar, 3Mori K. Cell. 2000; 101: 451-454Abstract Full Text Full Text PDF PubMed Scopus (783) Google Scholar, 4Urano F. Bertolotti A. Ron D. J. Cell Sci. 2000; 21: 3697-3702Google Scholar, 5Patil C. Walter P. Curr. Opin. Cell Biol. 2001; 13: 349-356Crossref PubMed Scopus (669) Google Scholar). These intracellular signaling pathways from the ER to the nucleus culminate in the activation of transcription of appropriate genes whose products are required to cope with the disturbance, leading to the maintenance of homeostasis. Sterol depletion activates certain basic helix-loop-helix-leucine zipper-type transcription factors, the sterol regulatory element-binding proteins (SREBP-1 and SREBP-2), by regulated intramembrane proteolysis (RIP). Thus, the precursor forms of SREBPs synthesized as transmembrane proteins in the ER are cleaved in response to sterol depletion so that the soluble N-terminal fragments of SREBPs released from the membrane (mature forms) enter the nucleus and activate the transcription of genes involved in cholesterol biosynthesis as well as receptor-mediated endocytosis of cholesterol-containing lipoproteins from plasma (6Yokoyama C. Wang X. Briggs M.R. Admon A. Wu J. Hua X. Goldstein J.L. Brown M.S. Cell. 1993; 75: 187-197Abstract Full Text PDF PubMed Scopus (776) Google Scholar, 7Wang X. Sato R. Brown M.S. Hua X. Goldstein J.L. Cell. 1994; 77: 53-62Abstract Full Text PDF PubMed Scopus (849) Google Scholar, 8DeBose-Boyd R.A. Brown M.S. Li W.P. Nohturfft A. Goldstein J.L. Espenshade P.J. Cell. 1999; 99: 703-712Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 9Brown M.S. Ye J. Rawson R.B. Goldstein J.L. Cell. 2000; 100: 391-398Abstract Full Text Full Text PDF PubMed Scopus (1135) Google Scholar). Cells cope with unfolded proteins accumulated in the ER under ER stress conditions primarily by transient attenuation of translation and by transcriptional induction of genes encoding ER-resident molecular chaperones (BiP/GRP78, GRP94 etc.) and folding enzymes (protein-disulfide isomerase, peptidyl-prolyl cis-trans isomerase, etc.), leading to augmenting the folding capacity in the ER. These processes are collectively termed the unfolded protein response (UPR) (2Kaufman R.J. Genes Dev. 1999; 13: 1211-1233Crossref PubMed Scopus (1912) Google Scholar, 3Mori K. Cell. 2000; 101: 451-454Abstract Full Text Full Text PDF PubMed Scopus (783) Google Scholar, 4Urano F. Bertolotti A. Ron D. J. Cell Sci. 2000; 21: 3697-3702Google Scholar, 5Patil C. Walter P. Curr. Opin. Cell Biol. 2001; 13: 349-356Crossref PubMed Scopus (669) Google Scholar). ER chaperones commonly contain in their promoter regions a unique cis-acting element designated as the ER stress response element (ERSE), whose consensus sequence is CCAAT-N9-CCACG; the ERSE is necessary and sufficient for the transcriptional induction of ER chaperone genes (10Yoshida H. Haze K. Yanagi H. Yura T. Mori K. J. Biol. Chem. 1998; 273: 33741-33749Abstract Full Text Full Text PDF PubMed Scopus (995) Google Scholar, 11Roy B. Lee A.S. Nucleic Acids Res. 1999; 27: 1437-1443Crossref PubMed Scopus (213) Google Scholar). As the general transcription factor NF-Y (CBF) constitutively occupies the CCAAT part of the ERSE (12Li W.W. Sistonen L. Morimoto R.I. Lee A.S. Mol. Cell. Biol. 1994; 14: 5533-5546Crossref PubMed Google Scholar), the binding of ER stress response factor(s) to the ERSE requires a component that is capable of binding to the CCACG part of the ERSE and that is specifically activated during the UPR. We previously identified the basic leucine zipper proteins ATF6α (encoded by the ATF6 gene) and ATF6β (encoded by the G13/cAMP response element-binding protein-related protein gene) as CCACG-binding proteins (10Yoshida H. Haze K. Yanagi H. Yura T. Mori K. J. Biol. Chem. 1998; 273: 33741-33749Abstract Full Text Full Text PDF PubMed Scopus (995) Google Scholar, 13Haze K. Okada T. Yoshida H. Yanagi H. Yura T. Negishi M. Mori K. Biochem. J. 2001; 355: 19-28Crossref PubMed Scopus (198) Google Scholar). Both ATF6α and ATF6β are constitutively synthesized as type II transmembrane glycoproteins that are anchored in the ER and are activated by proteolysis in response to ER stress (13Haze K. Okada T. Yoshida H. Yanagi H. Yura T. Negishi M. Mori K. Biochem. J. 2001; 355: 19-28Crossref PubMed Scopus (198) Google Scholar, 14Haze K. Yoshida H. Yanagi H. Yura T. Mori K. Mol. Biol. Cell. 1999; 10: 3787-3799Crossref PubMed Scopus (1488) Google Scholar). The N-terminal fragments thereby released from the membrane (mature forms of ATF6α and ATF6β) enter the nucleus and activate the transcription of their target genes via direct binding to the CCACG part of the ERSE in a manner dependent on the binding of NF-Y to the CCAAT part (15Yoshida H. Okada T. Haze K. Yanagi H. Yura T. Negishi M. Mori K. Mol. Cell. Biol. 2000; 20: 6755-6767Crossref PubMed Scopus (770) Google Scholar, 16Wang Y. Shen J. Arenzana R.J. R. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Google Scholar, H. Okada T. Haze K. Yanagi H. Yura T. Negishi M. Mori K. Mol. Cell. Biol. 2001; 21: PubMed Scopus Google Scholar). In this study, we used a to the of activation of ATF6α and ATF6β by ER and found that the serine protease 4-(2-aminoethyl)benzenesulfonyl fluoride ER stress-induced proteolysis of both ATF6α and ATF6β, resulting in inhibition of transcriptional induction of ATF6-target genes by ER stress. this was in Ye J. Rawson R.B. R. X. R. Brown M.S. Goldstein J.L. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) showed by transient that ER stress ATF6α is cleaved sequentially by the Site-1 protease and Site-2 protease which are known to SREBP sequentially in response to sterol S1P, also J. A. J. M. C. R.A. M. M. Sci. U. A. 1999; PubMed Scopus Google Scholar), is a serine protease with the is the membrane M.S. Ye J. Rawson R.B. Goldstein J.L. Cell. 2000; 100: 391-398Abstract Full Text Full Text PDF PubMed Scopus (1135) Google Scholar). Thus, two intracellular signaling from the ER to the nucleus SREBP and ATF6 molecular that in the ER to in the to the that ATF6 to relocate from the ER to the Golgi apparatus to be to SREBP, as is localized in the Golgi apparatus R.A. Brown M.S. Li W.P. Nohturfft A. Goldstein J.L. Espenshade P.J. Cell. 1999; 99: 703-712Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar). It was by transient that this is the X. Shen J. R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. X. L. R. Dev. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). We here for the first that ATF6 was from the ER to the nucleus via the Golgi apparatus in response to ER stress and that AEBSF blocked the nuclear translocation of ATF6 from the ER to the Golgi we that AEBSF inhibited Cell and cells in with and and in a protease inhibitors from and in or to the of and to J. T. Scholar). express the or of in the ER a of as for the ER by the and and was the and of to encoding the by and was the and of to The of the or of A. A. L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) was by with the in the and the and the and of to or their had been cells with these Cell to the and ATF6β with K. Yoshida H. Yanagi H. Yura T. Mori K. Mol. Biol. Cell. 1999; 10: 3787-3799Crossref PubMed Scopus (1488) Google Scholar) and (13Haze K. Okada T. Yoshida H. Yanagi H. Yura T. Negishi M. Mori K. Biochem. J. 2001; 355: 19-28Crossref PubMed Scopus (198) Google Scholar) was from and element-binding protein from cells in the as in the as previously T. Yoshida H. R. Negishi M. Mori K. Biochem. J. PubMed Scopus Google Scholar) and by the J. T. Scholar) was was first from cells with of of and then by with the as previously A. Y. Ron D. Cell Biol. 2000; PubMed Scopus Google Scholar). the of SREBP-2 in response to sterol depletion, cells for in with and as R. J. T. T. M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) and examined by a of SREBP-2 J. H. T. M. M. Sato R. Biochem. Res. 2001; PubMed Scopus Google Scholar). was by the of to and by J. T. Scholar) direct was cells on The cells with with for and with for then for in and in with or from Cell to the cells by of the cells for with immunoglobulin or immunoglobulin by of ER of ATF6α and ATF6β by various types of protease inhibitors to the of the protease for the of ATF6α and ATF6β from the precursor forms and to the mature forms and in response to ER stress. cells for with of the the by the and then for with which ER stress by inhibiting ER (2Kaufman R.J. Genes Dev. 1999; 13: 1211-1233Crossref PubMed Scopus (1912) Google Scholar). As a AEBSF, a serine protease inhibitor, was found to the production of and The effect of AEBSF was dependent on and with AEBSF was required to proteolysis of ATF6α and ATF6β It be that this of AEBSF was with used to in C. K. T. A. A. Y. Y. Y. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar) or to the of cells Cell Res. 2000; PubMed Scopus Google Scholar). In other serine protease inhibitors such as fluoride and showed effect a of that with AEBSF the but the production of both and in response to treatment that the for ATF6α and ATF6β in cells are to of the of various serine protease inhibitors on the of ATF6α and ATF6β induced by cells in for with of the serine protease inhibitors the and then with or of and as in the to The of and are of of and induction of and in cells with or AEBSF. cells with or AEBSF for and then with of AEBSF for the and by or as well as which The of and as well as are The of molecular are on the cells as in or with AEBSF for the was and by a to BiP, Asn-S, or of AEBSF on the the of AEBSF on the by the of a target of the UPR, which was induced by treatment both the protein and cells with AEBSF to the of induction of was the protein or that AEBSF as of the UPR. We also examined the of AEBSF on ER stress other and inhibitors of protein (2Kaufman R.J. Genes Dev. 1999; 13: 1211-1233Crossref PubMed Scopus (1912) Google Scholar), and which of proteins by (2Kaufman R.J. Genes Dev. 1999; 13: 1211-1233Crossref PubMed Scopus (1912) Google Scholar). As from results (13Haze K. Okada T. Yoshida H. Yanagi H. Yura T. Negishi M. Mori K. Biochem. J. 2001; 355: 19-28Crossref PubMed Scopus (198) Google Scholar, 14Haze K. Yoshida H. Yanagi H. Yura T. Mori K. Mol. Biol. Cell. 1999; 10: 3787-3799Crossref PubMed Scopus (1488) Google Scholar), the proteolysis of both ATF6α and ATF6β was by and as well as of cells with AEBSF blocked the proteolysis of ATF6α in response to treatment with or the effect of AEBSF on the of ATF6α induced by was we found that AEBSF inhibited the cleavage of ATF6α and ATF6β and the induction of by both the protein and and These results that the of ATF6α and ATF6β by a to AEBSF is a regulatory in the of of and induction of and in cells with or AEBSF. cells with or AEBSF for and then with of AEBSF for the and and as in the to and that AEBSF inhibited the proteolysis of ATF6α and ATF6β and induction of and protein in response to ER stress by accumulation of unfolded proteins in the ER. We examined the of AEBSF on ER stress-induced activation of a of attenuation that in response to ER stress Y. Ron D. 1999; PubMed Scopus Google Scholar, Y. Bertolotti A. H. Ron D. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). is a transmembrane protein activated by and activation can be by on A. Y. Ron D. Cell Biol. 2000; PubMed Scopus Google as shown with for AEBSF the activation of induced by with or 6 with that unfolded proteins accumulated under these conditions in the of AEBSF. In AEBSF the activation of induced by with or with with these the form of in cells with or was in the of AEBSF and Thus, AEBSF the of ER stress that accumulation of unfolded proteins in the ER by inhibiting protein the for these results is ER stress-induced activation of results in of the of factor leading to general attenuation Y. Ron D. 1999; PubMed Scopus Google Scholar, Y. Bertolotti A. H. Ron D. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). this attenuation translation of the basic leucine zipper transcription factor transcriptional induction of genes such as the basic leucine zipper transcription factor in response to ER stress Y. H. R. M. Ron D. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). We that the asparagine is also a target of the factor T. Yoshida H. R. Negishi M. Mori K. Biochem. J. PubMed Scopus Google Scholar). was induced in cells with or and was induced in cells with or we found that the induction of by or was or in cells with AEBSF the that was activated in these cells and 6, and that activation of the to a or of the induction of in cells with or Thus, AEBSF on the ATF6 but also the AEBSF must be used with of on of the UPR. of AEBSF on the of SREBP-2 and of ATF6 by been that ATF6α is cleaved by the enzymes that SREBPs J. Rawson R.B. R. X. R. Brown M.S. Goldstein J.L. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), we examined AEBSF can the of SREBP-2 in response to sterol As shown in 6, the of the mature form of was in nuclear of cells the cells with AEBSF as with AEBSF treatment of and the was as a and treatment with this a in the of in nuclear as previously X. Sato R. Brown M.S. Hua X. Goldstein J.L. Cell. 1994; 77: 53-62Abstract Full Text PDF PubMed Scopus (849) Google Scholar). the two enzymes that SREBP and but is a serine protease M.S. Ye J. Rawson R.B. Goldstein J.L. Cell. 2000; 100: 391-398Abstract Full Text Full Text PDF PubMed Scopus (1135) Google Scholar). We examined AEBSF It is known that is synthesized as a A. A. L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, P.J. D. Goldstein J.L. Brown M.S. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. C. M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of the sequence of a that is cleavage of the the two the from the form and thereby the and which are the form is localized in the Golgi apparatus as of the but form are to with P.J. D. Goldstein J.L. Brown M.S. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) or are A. A. L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was to be in the ER by the transmembrane of with the ER sequence soluble and was by resulting in cleavage of SREBP in a manner R.A. Brown M.S. Li W.P. Nohturfft A. Goldstein J.L. Espenshade P.J. Cell. 1999; 99: 703-712Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar). We such of soluble and in the ER cleavage of ATF6α and ATF6β in the of ER stress and AEBSF treatment can such cleavage of ATF6α and of S1P, the A. A. L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), as a The and used for this as under and designated and As shown in transient of and but and cells in of cleaved products of both ATF6α and ATF6β, which as a in both and As the of the was to that of or in response to treatment and we the as the or which ATF6α or ATF6β cleaved by but cleaved by the transmembrane These results that of and ATF6 in cleavage as in the of that of and We then examined the of AEBSF treatment on such cleavage of ATF6. As shown in the of was in cells with but in cells with as resulting in of of cleaved ATF6α and ATF6β in cells with with with the results shown in of cells the of the form of S1P, leading to of the of cleaved ATF6α and ATF6β in cells with and with such in cleavage was by the of AEBSF in the and These results that the target of AEBSF is S1P, which is a serine protease involved in the cleavage of both SREBP and ATF6. of AEBSF on ER of ATF6 examined AEBSF the intracellular transport of ATF6 in response to ER both SREBP and ATF6 from the ER to the nucleus via the Golgi apparatus, cleavage by and R.A. Brown M.S. Li W.P. Nohturfft A. Goldstein J.L. Espenshade P.J. Cell. 1999; 99: 703-712Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, J. X. L. R. Dev. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). As shown in in ATF6α was localized in that distinct from the with is a for Golgi apparatus J. M. 2000; PubMed Scopus Google as of treatment with ATF6 had in of treatment with the nucleus with In cells with AEBSF for the of ATF6α was from that in cells from ATF6α with the of treatment with and the nucleus was with in cells with AEBSF. These results indicate that the transport of ATF6 from the ER to the Golgi apparatus and that from the Golgi apparatus to the nucleus are distinct steps that can be distinguished by treatment with AEBSF is a M.S. Ye J. Rawson R.B. Goldstein J.L. Cell. 2000; 100: 391-398Abstract Full Text Full Text PDF PubMed Scopus (1135) Google Scholar). In transcription factor or a of a certain transcription factor is synthesized as a part of a transmembrane and from a precursor cells appropriate The thereby from the membrane by proteolysis the nucleus and activates or transcription of a of genes. is in the that the of form is by two of a precursor As the proteolysis is regulated and the cleavage the transmembrane this is regulated intramembrane of of a transmembrane protein from the this the to of a of genes such transcriptional is and is from to M.S. Ye J. Rawson R.B. Goldstein J.L. Cell. 2000; 100: 391-398Abstract Full Text Full Text PDF PubMed Scopus (1135) Google Scholar). In is to activate the stress a response to the in J. 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Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, proteins must relocate from the ER to the Golgi apparatus to be cleaved in response to of this in S1P, first can be constitutively under conditions in to In of was in the ER, SREBP was cleaved in the of R.A. Brown M.S. Li W.P. Nohturfft A. Goldstein J.L. Espenshade P.J. Cell. 1999; 99: 703-712Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar). We showed here that ATF6 was cleaved in the of ER stress of was in the ER the of a protein from the ER to be the in in to We showed in this that ER stress-induced proteolysis of ATF6α and ATF6β was prevented by of cells with AEBSF, a serine protease and AEBSF was in other such as cells As fragments of ATF6α and ATF6β in cells with AEBSF and and as sterol of SREBP-2 was also prevented by AEBSF is that AEBSF the first in the and that the target of AEBSF is was by the that AEBSF blocked cleavage of ATF6α and ATF6β induced by of the form of in the ER AEBSF on various ER stress other ATF6 we showed that ER stress-induced transport of ATF6 from the ER to the Golgi apparatus was inhibited by with AEBSF Thus, AEBSF a to the of activation of ATF6 by ER stress as It be that results are with in to of in which AEBSF known as was shown to as a form as with other protease inhibitors A. A. L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. Espenshade P.J. Brown M.S. Goldstein J.L. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). that the of ATF6 is by the ER chaperone under conditions and that of from ATF6 the of ATF6 from the ER under ER stress conditions as to unfolded proteins accumulated in the ER J. X. L. R. Dev. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). a to the of ATF6 activation is to the that in the of ATF6 in response to ER stress. to for such can be from cells or with various ER stress of AEBSF during ER stress treatment to directly the of the of the ER form with that of the Golgi ATF6 the Golgi resulting from the cleavage with the is now in We are to Ron for We and for and

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