ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors
Abstract
:1. Introduction
2. Materials and Methods
2.1. Plasmids, Antibodies, and Reagents
2.2. Cell Culture, Plasmids, Transfections, and Lysates
2.3. [35S] Metabolic Labeling
2.4. Media Conditioning, SDS-PAGE, CN-PAGE, and Immunoblotting
2.5. Quantification of FTTTR Tetramers in Conditioned Media
2.6. Co-Immunoprecipitation of FTTTRA25T
2.7. SILAC-MuDPIT Proteomics
3. Results
3.1. Stress-Independent ATF6 Activation Does Not Influence the Conformation of Secreted FTTTRA25T
3.2. ATF6 Activation Increases Interaction between FTTTRA25T and ER-Localized Proteostasis Factors
3.3. Overexpression of BiP or PDIA4 Reduces Secretion and Extracellular Aggregation of Destabilized FTTTRA25T
3.4. PDIA4 Overexpression Increases ER Retention of FTTTRA25T
3.5. PDIA4-Dependent Reductions in FTTTRA25T Secretion Is Independent of Cys10
3.6. Overexpression of Redox-Deficient PDIA4 Variants Decrease FTTTRA25T Secretion and Aggregation
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Mesgarzadeh, J.S.; Romine, I.C.; Smith-Cohen, E.M.; Grandjean, J.M.D.; Kelly, J.W.; Genereux, J.C.; Wiseman, R.L. ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors. Cells 2022, 11, 1661. https://doi.org/10.3390/cells11101661
Mesgarzadeh JS, Romine IC, Smith-Cohen EM, Grandjean JMD, Kelly JW, Genereux JC, Wiseman RL. ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors. Cells. 2022; 11(10):1661. https://doi.org/10.3390/cells11101661
Chicago/Turabian StyleMesgarzadeh, Jaleh S., Isabelle C. Romine, Ethan M. Smith-Cohen, Julia M. D. Grandjean, Jeffery W. Kelly, Joseph C. Genereux, and R. Luke Wiseman. 2022. "ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors" Cells 11, no. 10: 1661. https://doi.org/10.3390/cells11101661