Factor VIII exhibits chaperone-dependent and glucose-regulated reversible amyloid formation in the endoplasmic reticulum.

Blood
Juthakorn PoothongRandal J Kaufman

Abstract

Hemophilia A, an X-linked bleeding disorder caused by deficiency of factor VIII (FVIII), is treated by protein replacement. Unfortunately, this regimen is costly due to the expense of producing recombinant FVIII as a consequence of its low-level secretion from mammalian host cells. FVIII expression activates the endoplasmic reticulum (ER) stress response, causes oxidative stress, and induces apoptosis. Importantly, little is known about the factors that cause protein misfolding and aggregation in metazoans. Here, we identified intrinsic and extrinsic factors that cause FVIII to form aggregates. We show that FVIII forms amyloid-like fibrils within the ER lumen upon increased FVIII synthesis or inhibition of glucose metabolism. Significantly, FVIII amyloids can be dissolved upon restoration of glucose metabolism to produce functional secreted FVIII. Two ER chaperone families and their cochaperones, immunoglobulin binding protein (BiP) and calnexin/calreticulin, promote FVIII solubility in the ER, where the former is also required for disaggregation. A short aggregation motif in the FVIII A1 domain (termed Aggron) is necessary and sufficient to seed β-sheet polymerization, and BiP binding to this Aggron prevents amyloidogenesis. O...Continue Reading

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Citations

May 22, 2020·Blood·Denise E Sabatino
Nov 27, 2020·Blood·Margaret Ragni
Dec 15, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Jerry R MendellJacques P Tremblay
Feb 20, 2021·HemaSphere·Paul Batty, David Lillicrap
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Aug 11, 2020·Molecular Therapy. Methods & Clinical Development·Sylvia FongStuart Bunting
Mar 12, 2021·Cellular and Molecular Gastroenterology and Hepatology·Tirthadipa Pradhan-SunddMargaret V Ragni
Jul 22, 2021·International Journal of Laboratory Hematology·Paul Batty, David Lillicrap
Aug 15, 2021·Hematology/oncology Clinics of North America·Craig D SeamanMargaret V Ragni
Oct 1, 2021·Science·Margaret V Ragni

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