title: Accumulation of mutant alpha1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkappaB, and BAP31 but not the unfolded protein response.
abstract: In alpha(1)-antitrypsin (alpha1AT) deficiency, a polymerogenic mutant form of the secretory glycoprotein alpha1AT, alpha1ATZ, is retained in the endoplasmic reticulum (ER) of liver cells. It is not yet known how this results in liver injury in a subgroup of deficient individuals and how the remainder of deficient individuals escapes liver disease. One possible explanation is that the "susceptible" subgroup is unable to mount the appropriate protective cellular responses. Here we examined the effect of mutant alpha1ATZ on several potential protective signaling pathways by using cell lines with inducible expression of mutant alpha1AT as well as liver from transgenic mice with liver-specific inducible expression of mutant alpha1AT. The results show that ER retention of polymerogenic mutant alpha1ATZ does not result in an unfolded protein response (UPR). The UPR can be induced in the presence of alpha1ATZ by tunicamycin excluding the possibility that the pathway has been disabled. In striking contrast, ER retention of nonpolymerogenic alpha1AT mutants does induce the UPR. These results indicate that the machinery responsible for activation of the UPR can distinguish the physical characteristics of proteins that accumulate in the ER in such a way that it can respond to misfolded but not relatively ordered polymeric structures. Accumulation of mutant alpha1ATZ does activate specific signaling pathways, including caspase-12 in mouse, caspase-4 in human, NFkappaB, and BAP31, a profile that was distinct from that activated by nonpolymerogenic alpha1AT mutants.
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Tunda
authors.initials: T
authors.lastname: Hidvegi
authors.forename: Bela Z
authors.initials: BZ
authors.lastname: Schmidt
authors.forename: Pamela
authors.initials: P
authors.lastname: Hale
authors.forename: David H
authors.initials: DH
authors.lastname: Perlmutter
mesh_terms: D000818:Animals; D053454:Caspase 12; D020169:Caspases / Q000378:metabolism; D053471:Caspases, Initiator; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D017510:Protein Folding; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014415:Tunicamycin / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: C091247:BCAP31 protein, human; D008565:Membrane Proteins; D016328:NF-kappa B; D011994:Recombinant Proteins; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin; D014415:Tunicamycin; C506444:CASP12 protein, human; C093516:CASP4 protein, human; C506440:Casp12 protein, mouse; D053454:Caspase 12; D020169:Caspases; D053471:Caspases, Initiator