ATF6 Activation Reduces the Secretion and Extracellular Aggregation of Destabilized Variants of an Amyloidogenic Protein.pdf.pdf

Chemistry & Biology
Article
ATF6 Activation Reduces the Secretion
and Extracellular Aggregation of Destabilized
Variants of an Amyloidogenic Protein
John J. Chen,1,2 Joseph C. Genereux,1,2 Song Qu,1 John D. Hulleman,1,3 Matthew D. Shoulders,1,4 and R. Luke Wiseman1,*
1Department of Molecular and Experimental Medicine and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA
92037, USA
2Co-first author
3Present address: Departments of Ophthalmology and Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines
Boulevard, Dallas, TX 75390, USA
4Present address: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
*Correspondence: ******@
http://dx./.
SUMMARY (D’Arcangelo et al., 2013). Proteins unable to properly fold
in the ER lumen are targeted to ER degradation pathways
Systemic amyloidoses result from the aberrant including ER-associated degradation (ERAD) and autophagy
secretion of destabilized, amyloidogenic proteins to (Brodsky and Skach, 2011). This partitioning of ER targeted
the serum where they aggregate into proteotoxic sol- polypeptides between ER protein folding/trafficking and degra-
uble aggregates and amyloid fibrils. Few therapeutic dation pathways, also referred to as ER quality control, pre-
approaches exist to attenuate extracellular patho- vents the ER accumulation and secretion of misfolding-prone
logic aggregation of amyloidogenic proteins, neces- proteins that could aggregate into pathologic proteotoxic con-
formations (Brodsky and Skach, 2011; Gidalevitz et al., 2013;
sitating the development of new strategies to inter-
Powers et al., 2009).
vene in these devastating disorders. We show that While ER quality control is generally efficient at preventing the
stress-independent activation of the Unfolded Pro- secretion of aggregation-prone proteins, the aberrant secretion
t