Accumulation of mutant α1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFκB, and BAP31 but not the unfolded protein response

In alpha 1-antitrypsin (alpha 1AT) deficiency, a polymerogenic mutant form of the secretory glycoprotein alpha 1AT, alpha 1ATZ, 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 alpha 1ATZ on several potential protective signaling pathways by using cell lines with inducible expression of mutant alpha 1AT as well as liver from transgenic mice with liver-specific inducible expression of mutant alpha 1AT. The results show that ER retention of polymerogenic mutant alpha 1ATZ does not result in an unfolded protein response (UPR). The UPR can be induced in the presence of alpha 1ATZ by tunicamycin excluding the possibility that the pathway has been disabled. In striking contrast, ER retention of nonpolymerogenic alpha 1AT 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 alpha 1ATZ does activate specific signaling pathways, including caspase-12 in mouse, caspase-4 in human, NF kappa B, and BAP31, a profile that was distinct from that activated by nonpolymerogenic alpha 1AT mutants.