Neuroserpin Polymers Activate NF-κB by a Calcium Signaling Pathway That Is Independent of the Unfolded Protein Response

The autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies is characterized by the accumulation of ordered polymers of mutant neuroserpin within the endoplasmic reticulum of neurones. We show here that intracellular neuroserpin polymers activate NF-κB by a pathway that is independent of the IRE1, ATF6, and PERK limbs of the canonical unfolded protein response but is dependent on intracellular calcium. This pathway provides a mechanism for cells to sense and react to the accumulation of folded structures of mutant serpins within the endoplasmic reticulum. Our results provide strong support for the endoplasmic reticulum overload response being independent of the unfolded protein response. The autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies is characterized by the accumulation of ordered polymers of mutant neuroserpin within the endoplasmic reticulum of neurones. We show here that intracellular neuroserpin polymers activate NF-κB by a pathway that is independent of the IRE1, ATF6, and PERK limbs of the canonical unfolded protein response but is dependent on intracellular calcium. This pathway provides a mechanism for cells to sense and react to the accumulation of folded structures of mutant serpins within the endoplasmic reticulum. Our results provide strong support for the endoplasmic reticulum overload response being independent of the unfolded protein response. An increasing number of disorders are recognized to result from the aggregation and tissue deposition of misfolded proteins. Indeed, their shared mechanism provides the basis for a new class of disorder, the conformational diseases (1.Carrell R.W. Lomas D.A. Lancet. 1997; 350: 134-138Abstract Full Text Full Text PDF PubMed Scopus (820) Google Scholar). These include Alzheimer, Huntington, and Parkinson diseases as well as the amyloidoses and serpinopathies. The serpinopathies are characterized by the aggregation and tissue deposition of members of the serine protease inhibitor or serpin superfamily of proteins (2.Lomas D.A. Carrell R.W. Nat. Rev. Genet. 2002; 3: 759-768Crossref PubMed Scopus (197) Google Scholar). Point mutations of serpins such as α1-antitrypsin, antithrombin, and α1-antichymotrypsin result in a sequential linkage between the exposed mobile reactive center loop of one molecule and β-sheet A of another (3.Gooptu B. Hazes B. Chang W.S. Dafforn T.R. Carrell R.W. Read R.J. Lomas D.A. Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 67-72Crossref PubMed Scopus (177) Google Scholar, 4.Sivasothy P. Dafforn T.R. Gettins P.G. Lomas D.A. J. Biol. Chem. 2000; 275: 33663-33668Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). The resulting ordered polymers then accumulate as inclusion bodies within the lumen of the endoplasmic reticulum (ER) 5The abbreviations used are: ERendoplasmic reticulumFENIBfamilial encephalopathy with neuroserpin inclusion bodiesPERKPKR-like ER kinaseATF6activating transcription factor 6IRE1inositol-requiring kinase 1UPRunfolded protein responseERADER-associated degradationEORER overload responseGAPDHglyceraldehyde-3-phosphate dehydrogenaseWTwild typeTGthapsigarginANOVAanalysis of varianceBAPTA-AM1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester)OPRordered protein responseRLUrelative light unit(s)MEFmouse embryonic fibroblast. (1.Carrell R.W. Lomas D.A. Lancet. 1997; 350: 134-138Abstract Full Text Full Text PDF PubMed Scopus (820) Google Scholar, 2.Lomas D.A. Carrell R.W. Nat. Rev. Genet. 2002; 3: 759-768Crossref PubMed Scopus (197) Google Scholar). This is associated with disease due to loss of function (i.e. the reduction in active protein) and/or a toxic gain of function (i.e. the cytotoxicity of protein aggregates). endoplasmic reticulum familial encephalopathy with neuroserpin inclusion bodies PKR-like ER kinase activating transcription factor 6 inositol-requiring kinase 1 unfolded protein response ER-associated degradation ER overload response glyceraldehyde-3-phosphate dehydrogenase wild type thapsigargin analysis of variance 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester) ordered protein response relative light unit(s) mouse embryonic fibroblast. One of the most striking serpinopathies is the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB (5.Davis R.L. Shrimpton A.E. Holohan P.D. Bradshaw C. Feiglin D. Collins G.H. Sonderegger P. Kinter J. Becker L.M. Lacbawan F. Krasnewich D. Muenke M. Lawrence D.A. Yerby M.S. Shaw C.M. Gooptu B. Elliott P.R. Finch J.T. Carrell R.W. Lomas D.A. Nature. 1999; 401: 376-379Crossref PubMed Google Scholar). This results from one of four naturally occurring point mutations in the neuroserpin gene: S49P, S52R, H338R, or G392E (6.Davis R.L. Shrimpton A.E. Carrell R.W. Lomas D.A. Gerhard L. Baumann B. Lawrence D.A. Yepes M. Kim T.S. Ghetti B. Piccardo P. Takao M. Lacbawan F. Muenke M. Sifers R.N. Bradshaw C.B. Kent P.F. Collins G.H. Larocca D. Holohan P.D. Lancet. 2002; 359: 2242-2247Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). The mutant neuroserpin proteins form ordered polymers that accumulate in the ER of neurones within the cerebral cortex, hippocampus, and substantia nigra (5.Davis R.L. Shrimpton A.E. Holohan P.D. Bradshaw C. Feiglin D. Collins G.H. Sonderegger P. Kinter J. Becker L.M. Lacbawan F. Krasnewich D. Muenke M. Lawrence D.A. Yerby M.S. Shaw C.M. Gooptu B. Elliott P.R. Finch J.T. Carrell R.W. Lomas D.A. Nature. 1999; 401: 376-379Crossref PubMed Google Scholar, 6.Davis R.L. Shrimpton A.E. Carrell R.W. Lomas D.A. Gerhard L. Baumann B. Lawrence D.A. Yepes M. Kim T.S. Ghetti B. Piccardo P. Takao M. Lacbawan F. Muenke M. Sifers R.N. Bradshaw C.B. Kent P.F. Collins G.H. Larocca D. Holohan P.D. Lancet. 2002; 359: 2242-2247Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 7.Davis R.L. Holohan P.D. Shrimpton A.E. Tatum A.H. Daucher J. Collins G.H. Todd R. Bradshaw C. Kent P. Feiglin D. Rosenbaum A. Yerby M.S. Shaw C.M. Lacbawan F. Lawrence D.A. Am J. Pathol. 1999; 155: 1901-1913Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). The resulting inclusions lead to progressive dementia, with the age of onset of disease being inversely proportional to the rate at which the mutants form polymers in vitro and the number of intra-cerebral inclusions (6.Davis R.L. Shrimpton A.E. Carrell R.W. Lomas D.A. Gerhard L. Baumann B. Lawrence D.A. Yepes M. Kim T.S. Ghetti B. Piccardo P. Takao M. Lacbawan F. Muenke M. Sifers R.N. Bradshaw C.B. Kent P.F. Collins G.H. Larocca D. Holohan P.D. Lancet. 2002; 359: 2242-2247Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). The accumulation of misfolded proteins within the lumen of the ER activates the PERK (PKR-like ER kinase), IRE1 (inositol-requiring kinase 1), and ATF6 (activating transcription factor 6) limbs of the unfolded protein response (UPR). This pathway serves to attenuate protein translation and increase the production of molecular chaperones to promote polypeptide folding and remove terminally misfolded proteins by ER-associated degradation (ERAD) (8.Ron D. Walter P. Nat. Rev. Mol. Cell Biol. 2007; 8: 519-529Crossref PubMed Scopus (4929) Google Scholar). The UPR is increasingly being implicated in the pathogenesis of human disease (9.Marciniak S.J. Ron D. Physiol. Rev. 2006; 86: 1133-1149Crossref PubMed Scopus (788) Google Scholar). It is striking that accumulation of mutant Z α1-antitrypsin polymers within the ER of hepatocytes does not elicit the UPR (10.Graham K.S. Le A. Sifers R.N. J. Biol. Chem. 1990; 265: 20463-20468Abstract Full Text PDF PubMed Google Scholar) but does activate NF-κB (11.Hidvegi T. Schmidt B.Z. Hale P. Perlmutter D.H. J. Biol. Chem. 2005; 280: 39002-39015Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 12.Lawless M.W. Greene C.M. Mulgrew A. Taggart C.C. O'Neill S.J. McElvaney N.G. J. Immunol. 2004; 172: 5722-5726Crossref PubMed Scopus (167) Google Scholar). This has been explained by the activation of the ER overload response (EOR) (13.Pahl H.L. Baeuerle P.A. EMBO J. 1995; 14: 2580-2588Crossref PubMed Scopus (353) Google Scholar), a stress signaling pathway that links the accumulation of folded proteins within the ER with the activation of NF-κB. The term EOR was originally coined to describe the NF-κB response to ER accumulation of viral proteins (14.Pahl H.L. Sester M. Burgert H.G. Baeuerle P.A. J. Cell Biol. 1996; 132: 511-522Crossref PubMed Scopus (153) Google Scholar), but was subsequently extended to include other proteins retained within the ER despite achieving native or near native conformations (15.Knorre A. Wagner M. Schaefer H.E. Colledge W.H. Pahl H.L. Biol. Chem. 2002; 383: 271-282Crossref PubMed Scopus (61) Google Scholar, 16.Pahl H.L. Physiol. Rev. 1999; 79: 683-701Crossref PubMed Scopus (307) Google Scholar). However, NF-κB activation in response to ER dysfunction has been shown to require PERK signaling, and so the very existence of an EOR pathway distinct from the UPR remains controversial (17.Deng J. Lu P.D. Zhang Y. Scheuner D. Kaufman R.J. Sonenberg N. Harding H.P. Ron D. Mol. Cell. Biol. 2004; 24: 10161-10168Crossref PubMed Scopus (524) Google Scholar). Here we have used wild-type and mutants of neuroserpin to investigate the consequences of ordered protein accumulation within the ER. We demonstrate that neuroserpin polymers activate NF-κB by a calcium-dependent pathway that is independent of the IRE, ATF6, and PERK limbs of the canonical UPR. These data provide strong support for a signaling pathway that directly links the activation of NF-κB with the accumulation of ordered proteins within the ER. The rabbit polyclonal anti-neuroserpin antibody was produced by Abcam (Cambridge, UK) using purified recombinant wild-type neuroserpin as the antigen (18.Belorgey D. Crowther D.C. Mahadeva R. Lomas D.A. J. Biol. Chem. 2002; 277: 17367-17373Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). Rabbit polyclonal anti-GAPDH and donkey polyclonal anti-rabbit IgG (Texas Red) antibodies were also from Abcam. Goat polyclonal anti-rabbit IgG (horseradish peroxidase) and rabbit polyclonal anti-mouse IgG (horseradish peroxidase) antibodies were from Sigma-Aldrich. Rabbit polyclonal anti-Phospho-eIF2α (S51) from Cell Signaling was a kind gift from Dr. Shiu-Wan Chan (Faculty of Life Sciences, University of Manchester, UK). All pharmacological cell-permeable inhibitors were purchased from Calbiochem (Merck Chemicals Ltd., Nottingham, UK). Unless stated otherwise, reagents for cell culture were purchased from Sigma-Aldrich. The cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% v/v heat-inactivated horse serum, 5% v/v Tet Approved Fetal Bovine Serum (BD Biosciences), 10 mm HEPES, 1× non-essential amino acids, 0.2 unit/ml bovine insulin, 200 and from and at and 5% v/v in a was with 10 (BD wild-type and were with S52R, and neuroserpin using 1997; PubMed Scopus Google Scholar, P.D. C. S.J. Zhang Y. Scheuner D. Kaufman R.J. Ron D. Harding H.P. 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Ron D. 2004; PubMed Scopus Google Scholar). were in that been with of or and of kind from Dr. were with of in culture medium the The cells were using the in 1× and were using a and was relative to All were in cells were at a of 1 and with to the for at and then at The cells were then a cell (BD and at was by the of 1 thapsigargin and the to a relative increase in that was cells were with for or the was by the of 1 for and for 1 in All were in and with (BD within a for the of a on cell a was data between then with a was the to the of mutant we used cell that wild-type human neuroserpin or the and G392E mutants that are associated with and of the dementia J. Crowther D.C. Lomas D.A. Mol. Genet. PubMed Scopus Google Scholar) we a cell that a mutant of with of the amino acids, which include the reactive loop This mutant is to the of the serpin α1-antitrypsin, which form ordered polymers and is an of the UPR and a for R.N. J. Biol. Chem. Full Text PDF PubMed Google Scholar). We the of neuroserpin in cells by and analysis All four cell neuroserpin the cells were with increasing of S52R, and G392E neuroserpin with a molecular of the of at Our that in cell neuroserpin was in at the of of a protein the pathway J. Crowther D.C. Lomas D.A. Mol. Genet. PubMed Scopus Google Scholar). and G392E neuroserpin inclusions within the ER that were to polymers Lomas D.A. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (100) Google Scholar, J. Crowther D.C. Lomas D.A. Mol. Genet. PubMed Scopus Google Scholar). neuroserpin ER but was within the not that of the misfolded mutant protein was of the ER. We neuroserpin from cell by with by of and neuroserpin was the culture medium by with and of and G392E neuroserpin was not in the culture medium despite being from the cell within 1 of We that neuroserpin a for we the degradation of neuroserpin by in the or of the W.S. 1995; PubMed Scopus Google or P. PubMed Scopus Google Scholar, PubMed Scopus Google with intracellular S52R, and neuroserpin by and and with on the intracellular of neuroserpin protease a in the degradation of mutant neuroserpin and data demonstrate that neuroserpin the pathway and that and G392E neuroserpin are and retained within the ER of cell neuroserpin is in the ER but by a being the We characterized the of the proteins retained within the ER to 10 of by and analysis of cell neuroserpin as a and G392E neuroserpin the molecular that are of serpin polymers native and A of neuroserpin as a S52R, we the of neuroserpin by we not due to of mutant protein and/or the of misfolded protein to by the mutants of neuroserpin within the we their on the UPR. of the proteins the UPR as by of protein protein and protein a canonical UPR that an increase in the of ER chaperones were from the and for the of protein a transcription factor by the UPR S.J. Zhang Y. R. Harding H.P. Ron D. 2004; PubMed Scopus Google Scholar, Y. L.M. J. 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Chem. 2005; 280: 39002-39015Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 12.Lawless M.W. Greene C.M. Mulgrew A. Taggart C.C. O'Neill S.J. McElvaney N.G. J. Immunol. 2004; 172: 5722-5726Crossref PubMed Scopus (167) Google Scholar). We the accumulation of neuroserpin also activate transcription The cell neuroserpin were with 10 and subsequently with the NF-κB and the We of NF-κB activation in cells and neuroserpin and with The of and G392E in of NF-κB activation and G392E with was increase in NF-κB activation the of that NF-κB activation does not the accumulation of The of from cells and G392E neuroserpin to cells for 10 not activate NF-κB. to IRE1 and ATF6, UPR signaling the kinase PERK H.P. Zhang Y. Ron D. Nature. 1999; PubMed Scopus Google Scholar, H.P. Zhang Y. A. Ron D. Mol. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), which has been shown to activate NF-κB by the of (17.Deng J. Lu P.D. Zhang Y. Scheuner D. Kaufman R.J. Sonenberg N. Harding H.P. Ron D. Mol. Cell. Biol. 2004; 24: 10161-10168Crossref PubMed Scopus (524) Google Scholar, D. B. C. R. P. T. Kaufman R.J. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, Scheuner D. Kaufman R.J. Mol. Cell. Biol. PubMed Scopus Google Scholar). We polymers of neuroserpin activate NF-κB of the PERK of the UPR by using in which of serine to to by PERK D. B. C. R. P. T. Kaufman R.J. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). and were with 1 thapsigargin for to that the cells serine the UPR is The and cells were with or S52R, or of neuroserpin cells were with and neuroserpin were in the cell by and The of neuroserpin were in cell and culture for and cells and a which activates of the NF-κB in and cells the cell NF-κB in response to the UPR activating the of in activation but not in signaling thapsigargin The of neuroserpin cells were then with the NF-κB and and the relative of NF-κB were The cells and cells neuroserpin not activate the NF-κB and cells were to activate NF-κB in the but was in cell in in that in NF-κB activation is the PERK of the UPR. the and G392E neuroserpin cell were to activate NF-κB in and cell and These data provide that the accumulation of ordered protein polymers within the ER activate NF-κB of the canonical UPR signaling of NF-κB has been shown to dependent on (13.Pahl H.L. Baeuerle P.A. EMBO J. 1995; 14: 2580-2588Crossref PubMed Scopus (353) Google Scholar, M. N.G. J. Cell Biol. PubMed Scopus Google Scholar, A. A. Mol. Cell. Biol. PubMed Scopus Google Scholar). We the cell to neuroserpin with of or intracellular calcium. of on the of NF-κB in of the cell intracellular in a reduction in NF-κB signaling in cells S52R, and neuroserpin These and on the of the mutants to form polymers not for toxic of the the of cells with we cells with another to the We that which does not intracellular to activation of the not the mutants of neuroserpin also a to with 1 thapsigargin with that accumulation ER A of intracellular increase in response to thapsigargin was between and G392E cells in medium not This that the of G392E neuroserpin is on the of ER from the data show that NF-κB in response to the accumulation of neuroserpin polymers within the ER is dependent on to the The serpinopathies are the conformational diseases in that result from the of ordered unfolded within the ER of the cell of (1.Carrell R.W. Lomas D.A. Lancet. 1997; 350: 134-138Abstract Full Text Full Text PDF PubMed Scopus (820) Google Scholar, 2.Lomas D.A. Carrell R.W. Nat. Rev. Genet. 2002; 3: 759-768Crossref PubMed Scopus (197) Google Scholar). This is most in the dementia FENIB that is characterized by the of polymers of neuroserpin as inclusions or bodies (5.Davis R.L. Shrimpton A.E. Holohan P.D. Bradshaw C. Feiglin D. Collins G.H. Sonderegger P. Kinter J. Becker L.M. Lacbawan F. Krasnewich D. Muenke M. Lawrence D.A. Yerby M.S. Shaw C.M. Gooptu B. Elliott P.R. Finch J.T. Carrell R.W. Lomas D.A. Nature. 1999; 401: 376-379Crossref PubMed Google Scholar, 6.Davis R.L. Shrimpton A.E. Carrell R.W. Lomas D.A. Gerhard L. Baumann B. Lawrence D.A. Yepes M. Kim T.S. Ghetti B. Piccardo P. Takao M. Lacbawan F. Muenke M. Sifers R.N. Bradshaw C.B. Kent P.F. Collins G.H. Larocca D. Holohan P.D. Lancet. 2002; 359: 2242-2247Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). We have the of intracellular inclusions in cell that mutants that and of and a of neuroserpin that is a for cell neuroserpin was the as we have shown J. Crowther D.C. Lomas D.A. Mol. Genet. PubMed Scopus Google Scholar), the neuroserpin was by with a of This is to the of the of α1-antitrypsin R.N. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The and G392E mutants of neuroserpin that FENIB (6.Davis R.L. Shrimpton A.E. Carrell R.W. Lomas D.A. Gerhard L. Baumann B. Lawrence D.A. Yepes M. Kim T.S. Ghetti B. Piccardo P. Takao M. Lacbawan F. Muenke M. Sifers R.N. Bradshaw C.B. Kent P.F. Collins G.H. Larocca D. Holohan P.D. Lancet. 2002; 359: 2242-2247Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar) were retained as polymers within the ER as shown Lomas D.A. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus (100) Google Scholar). of neuroserpin mutants cells were with the inhibitors and and results not This that is a of and G392E mutant neuroserpin that by the of degradation on the of and G392E This that not as in the degradation of neuroserpin polymers in to polymers of Z α1-antitrypsin J. Cell Sci. PubMed Scopus Google Scholar, Perlmutter D.H. J. Physiol. Physiol. 2000; PubMed Google Scholar). The of polymers of and G392E neuroserpin within the ER on the of the ER chaperones protein or protein These chaperones were intracellular of mutant proteins were by not The of neuroserpin that the of ER chaperones were to of proteins within the ER. neuroserpin was to elicit the of intracellular were by polymers of mutant neuroserpin on their were with the This of UPR activation neuroserpin accumulation was also characterized by a on the or the accumulation of neuroserpin within the ER not of or activation of ATF6, activate NF-κB This activation of NF-κB was to that for cell and mouse of α1-antitrypsin (11.Hidvegi T. Schmidt B.Z. Hale P. Perlmutter D.H. J. Biol. Chem. 2005; 280: 39002-39015Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 12.Lawless M.W. Greene C.M. Mulgrew A. Taggart C.C. O'Neill S.J. McElvaney N.G. J. Immunol. 2004; 172: 5722-5726Crossref PubMed Scopus (167) Google Scholar). has shown that the activation of the UPR NF-κB signaling PERK (17.Deng J. Lu P.D. Zhang Y. Scheuner D. Kaufman R.J. Sonenberg N. Harding H.P. Ron D. Mol. Cell. Biol. 2004; 24: 10161-10168Crossref PubMed Scopus (524) Google Scholar, Scheuner D. Kaufman R.J. Mol. Cell. Biol. PubMed Scopus Google Scholar). We used cells in the PERK signaling of the UPR to activation of NF-κB in of but not the were to activate NF-κB in cells These data that neuroserpin polymers activate NF-κB by a pathway that is independent of the canonical UPR This is of an ER to signaling pathway that has been the EOR (13.Pahl H.L. Baeuerle P.A. EMBO J. 1995; 14: 2580-2588Crossref PubMed Scopus (353) Google Scholar, H.L. Sester M. Burgert H.G. Baeuerle P.A. J. Cell Biol. 1996; 132: 511-522Crossref PubMed Scopus (153) Google Scholar, H.L. Baeuerle P.A. Sci. 1997; Full Text PDF PubMed Scopus Google Scholar). The EOR was in the of protein and mutant of accumulation and has been as the signaling pathway that accumulation of α1-antitrypsin polymers within hepatocytes (11.Hidvegi T. Schmidt B.Z. Hale P. Perlmutter D.H. J. Biol. Chem. 2005; 280: 39002-39015Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 12.Lawless M.W. Greene C.M. Mulgrew A. Taggart C.C. O'Neill S.J. McElvaney N.G. J. Immunol. 2004; 172: 5722-5726Crossref PubMed Scopus (167) Google Scholar). Our results support the existence of a ER pathway that activates NF-κB. The term overload (13.Pahl H.L. Baeuerle P.A. EMBO J. 1995; 14: 2580-2588Crossref PubMed Scopus (353) Google Scholar), not the most to describe serpin activation of NF-κB. This is the overload of protein that of the ER associated with a reduction in ER and/or of and the of ER stress M. M. Cell 2002; PubMed Scopus Google Scholar, M. A. 2000; PubMed Scopus Google Scholar). were in the ER by accumulation in cell that the term not the term EOR does not between misfolded such as (15.Knorre A. Wagner M. Schaefer H.E. Colledge W.H. Pahl H.L. Biol. Chem. 2002; 383: 271-282Crossref PubMed Scopus (61) Google Scholar) or folded such as viral inclusions (14.Pahl H.L. Sester M. Burgert H.G. Baeuerle P.A. J. Cell Biol. 1996; 132: 511-522Crossref PubMed Scopus (153) Google Scholar) or polymers of neuroserpin and We that protein a for pathway to with the unfolded protein response (UPR). The EOR is associated with of intracellular A. A. Mol. Cell. Biol. PubMed Scopus Google Scholar, H.L. Baeuerle P.A. 1996; PubMed Scopus Google Scholar, Y. J. Cell. Physiol. 2005; PubMed Scopus Google Scholar, B. O'Neill J. Immunol. 1995; 155: Google Scholar, A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). We the of and on the UPR and activation of NF-κB. of on or activation of NF-κB. signaling of NF-κB was by the of intracellular This was most striking for the cell and G392E The intracellular for in the cell was was from the ER by the of 1 These results that ER is in the activation of NF-κB in the by the neuroserpin cell the culture on the of NF-κB in from the of intracellular the activation of NF-κB by mutant accumulation in cells is by a calcium-dependent in the from the ER to the we have the signaling that activate the transcription factor NF-κB the accumulation of polymers of neuroserpin within the ER. This the existence of a pathway that to the but for we to the ordered protein response or This pathway is also to by the accumulation of ordered polymers of mutant and in other serpinopathies. activation of NF-κB in response to polymers such as and Nat. Rev. Mol. Cell Biol. 2007; 8: PubMed Scopus Google Scholar). However, activation of NF-κB to the cell that the accumulation of polymers of neuroserpin and to dementia and We are to Dr. for the and M. J. D. to members of the Lomas and Dr. for and with