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

• Published in: The Journal of biological chemistry Vol. 284; no. 27; pp. 18202 - 18209
• Main Authors: Davies, Mark J., Miranda, Elena, Roussel, Benoit D., Kaufman, Randal J., Marciniak, Stefan J., Lomas, David A.
• Format: Journal Article
• Language: English
• Published: 9650 Rockville Pike, Bethesda, MD 20814, U.S.A Elsevier Inc 03.07.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Protein Synthesis, Post-Translational Modification, and Degradation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.010744

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.