Neuroserpin polymers activate NF-kappaB 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-kappaB 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.
Davies
Mark J
MJ
Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge CB2 0XY, United Kingdom.
Miranda
Elena
E
Roussel
Benoit D
BD
Kaufman
Randal J
RJ
Marciniak
Stefan J
SJ
Lomas
David A
DA
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002461:Cell Line, Transformed; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D016296:Mutagenesis; D016328:NF-kappa B / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation / Q000502:physiology; D011108:Polymers / Q000378:metabolism; D017510:Protein Folding; D011817:Rabbits; D051381:Rats; D015843:Serpins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014162:Transfection; D000097522:Neuroserpin
D000906:Antibodies; D002118:Calcium; D015852:Eukaryotic Initiation Factor-2; D016328:NF-kappa B; D009479:Neuropeptides; D011108:Polymers; D015843:Serpins; D000097522:Neuroserpin