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

Davies, Mark; Miranda, Elena; Roussel, Benoit D.; Kaufman, Randal J.; Marciniak, Stefan J.; Lomas, David A.

doi:10.1074/jbc.m109.010744

Cited by 68 publications

(124 citation statements)

References 46 publications

Supporting

Mentioning

113

Contrasting

Order By: Relevance

“…Beneficial effects of active ATF6 in the clearance of serpin polymers have recently been shown in cells thus supporting our finding of selective UPR activity (Smith et al 2011). The induction of all three branches of the UPR is controversial for serpinopathies, with several reports showing absence (Davies et al 2009; Kroeger et al 2009) or presence of the UPR (Lawless et al 2004). Instead, an ER stress response distinct from classical UPR signaling has been reported (Davies et al 2009).…”

supporting

confidence: 70%

“…The transient, agedependent induction of the UPR suggests the necessity of a second insult, possibly aging, to mount an UPR response. This finding unifies current concepts of disturbed proteostasis in FENIB (Lawless et al 2004;Hidvegi et al 2005;Davies et al 2009). Since IRE1 signaling has been linked to autophagy, the relatively low induction of IRE1 signaling in our murine FENIB model may help to explain the fact that autophagy is only mildly increased in FENIB (Hetz et al 2009;Kroeger et al 2009).…”

supporting

confidence: 49%

“…Indeed, aggregated SRP-2 H302R accumulates around the nucleus, suggesting a related localization in the ER as shown for mutant neuroserpin in mice ( Figure 1C and Figure 4A) (Galliciotti et al 2007). It is known that ER accumulation of misfolded proteins leads to ER stress and induction of the UPR, although for serpins this requires a second insult (Hidvegi et al 2005;Marciniak and Ron 2006;Davies et al 2009). Therefore, we investigated the importance of different stress response pathways and monitored SRP-2 H302R aggregation in the absence of the central transcription factor HSF-1, regulating the heat shock response or one of the three different pathways of the UPR that require IRE-1, ATF-6, and PEK-1 (PERK in mammals), respectively.…”

Section: Defects In the Upr Cause Enhanced Srp-2 Aggregation In Wormsmentioning

confidence: 99%

“…The induction of all three branches of the UPR is controversial for serpinopathies, with several reports showing absence (Davies et al 2009; Kroeger et al 2009) or presence of the UPR (Lawless et al 2004). Instead, an ER stress response distinct from classical UPR signaling has been reported (Davies et al 2009). The transient, agedependent induction of the UPR suggests the necessity of a second insult, possibly aging, to mount an UPR response.…”

mentioning

confidence: 99%

See 3 more Smart Citations

A Novel Interaction Between Aging and ER Overload in a Protein Conformational Dementia

et al. 2013

Self Cite

View full text Add to dashboard Cite

Intraneuronal deposition of aggregated proteins in tauopathies, Parkinson disease, or familial encephalopathy with neuroserpin inclusion bodies (FENIB) leads to impaired protein homeostasis (proteostasis). FENIB represents a conformational dementia, caused by intraneuronal polymerization of mutant variants of the serine protease inhibitor neuroserpin. In contrast to the aggregation process, the kinetic relationship between neuronal proteostasis and aggregation are poorly understood. To address aggregate formation dynamics, we studied FENIB in Caenorhabditis elegans and mice. Point mutations causing FENIB also result in aggregation of the neuroserpin homolog SRP-2 most likely within the ER lumen in worms, recapitulating morphological and biochemical features of the human disease. Intriguingly, we identified conserved protein quality control pathways to modulate protein aggregation both in worms and mice. Specifically, downregulation of the unfolded protein response (UPR) pathways in the worm favors mutant SRP-2 accumulation, while mice overexpressing a polymerizing mutant of neuroserpin undergo transient induction of the UPR in young but not in aged mice. Thus, we find that perturbations of proteostasis through impairment of the heat shock response or altered UPR signaling enhance neuroserpin accumulation in vivo. Moreover, accumulation of neuroserpin polymers in mice is associated with an age-related induction of the UPR suggesting a novel interaction between aging and ER overload. These data suggest that targets aimed at increasing UPR capacity in neurons are valuable tools for therapeutic intervention.

show abstract

supporting

confidence: 70%

supporting

confidence: 49%

Section: Defects In the Upr Cause Enhanced Srp-2 Aggregation In Wormsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

A Novel Interaction Between Aging and ER Overload in a Protein Conformational Dementia

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…Instead Z α 1 -antitrypsin expression activates NFκB by a calcium-mediated pathway that is independent of the UPR [32][33][34][35]. We have termed this the 'ordered protein response' [35] and others have shown that it results in the release of IL-6 and IL-8 [34].…”

Section: Intracellular Processing Of α α α α 1 -Antitrypsin Polymersmentioning

confidence: 99%

Update on alpha-1 antitrypsin deficiency: New therapies

Lomas

Hurst

Gooptu

2016

Journal of Hepatology

Self Cite

View full text Add to dashboard Cite

α 1 -antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α 1 -antitrypsin within the endoplasmic reticulum of hepatocytes. The retention of mutant protein causes hepatic damage and cirrhosis whilst the lack of an important circulating protease inhibitor predisposes the individuals with severe α 1 -antitrypsin deficiency to early onset emphysema. Our work over the past 25 years has led to new paradigms for the liver and lung disease associated with α 1 -antitrypsin deficiency. We review here the molecular pathology of the cirrhosis and emphysema associated with α 1 -antitrypsin deficiency and show how an understanding of this condition provided the paradigm for a wider group of disorders that we have termed the serpinopathies.The detailed understanding of the pathobiology of α 1 -antitrypsin deficiency has identified important disease mechanisms to target. As a result, several novel parallel and complementary therapeutic approaches are in development with some now in clinical trials.We provide an overview of these new therapies for the liver and lung disease associated with α 1 -antitrypsin deficiency.

show abstract

Familial Encephalopathy with Neuroserpin Inclusion Bodies

Davis

Collins

2011

Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders

View full text Add to dashboard Cite

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

Cited by 68 publications

References 46 publications

A Novel Interaction Between Aging and ER Overload in a Protein Conformational Dementia

A Novel Interaction Between Aging and ER Overload in a Protein Conformational Dementia

Update on alpha-1 antitrypsin deficiency: New therapies

Familial Encephalopathy with Neuroserpin Inclusion Bodies

Contact Info

Product

Resources

About