Cellular stress due to impairment of collagen prolyl hydroxylation complex is rescued by the chaperone 4-phenylbutyrate
Roberta Besio,Nadia Garibaldi,Laura Leoni,Lina Cipolla,Simone Sabbioneda,Marco Biggiogera,Monica Mottes,Mona Aglan,Ghada A. Otaify,Samia A. Temtamy,Antonio Rossi,Antonella Forlino +11 more
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TLDR
It is proved that the rescue of cellular homeostasis following 4-PBA treatment is associated with its chaperone activity, since it increases protein secretion, restoring ER proteostasis and reducing PERK activation and cell survival also in the presence of pharmacological inhibition of autophagy.Abstract:
Osteogenesis imperfecta (OI) types VII, VIII and IX, caused by recessive mutations in cartilage-associated protein (CRTAP), prolyl-3-hydroxylase 1 (P3H1) and cyclophilin B (PPIB), respectively, are characterized by the synthesis of overmodified collagen. The genes encode for the components of the endoplasmic reticulum (ER) complex responsible for the 3-hydroxylation of specific proline residues in type I collagen. Our study dissects the effects of mutations in the proteins of the complex on cellular homeostasis, using primary fibroblasts from seven recessive OI patients. In all cell lines, the intracellular retention of overmodified type I collagen molecules causes ER enlargement associated with the presence of protein aggregates, activation of the PERK branch of the unfolded protein response and apoptotic death. The administration of 4-phenylbutyrate (4-PBA) alleviates cellular stress by restoring ER cisternae size, and normalizing the phosphorylated PERK (p-PERK):PERK ratio and the expression of apoptotic marker. The drug also has a stimulatory effect on autophagy. We proved that the rescue of cellular homeostasis following 4-PBA treatment is associated with its chaperone activity, since it increases protein secretion, restoring ER proteostasis and reducing PERK activation and cell survival also in the presence of pharmacological inhibition of autophagy. Our results provide a novel insight into the mechanism of 4-PBA action and demonstrate that intracellular stress in recessive OI can be alleviated by 4-PBA therapy, similarly to what we recently reported for dominant OI, thus allowing a common target for OI forms characterized by overmodified collagen.This article has an associated First Person interview with the first author of the paper.read more
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CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta.
Roy Morello,Terry Bertin,Yuqing Chen,Yuqing Chen,John Hicks,Laura Tonachini,Massimiliano Monticone,Patrizio Castagnola,Frank Rauch,Frank Rauch,Francis H. Glorieux,Francis H. Glorieux,Janice A. Vranka,Janice A. Vranka,Hans Peter Bächinger,Hans Peter Bächinger,James M. Pace,Ulrike Schwarze,Peter H. Byers,MaryAnn Weis,Russell J. Fernandes,David R. Eyre,Zhenqiang Yao,Brendan F. Boyce,Brendan Lee,Brendan Lee,Brendan Lee +26 more
TL;DR: In humans, CRTAP mutations are associated with the clinical spectrum of recessive osteogenesis imperfecta, including the type II and VII forms, and dysregulation of prolyl 3-hydroxylation is a mechanism for connective tissue disease.
Journal ArticleDOI
Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta
Wayne A. Cabral,Weizhong Chang,Aileen M. Barnes,MaryAnn Weis,Melissa A Scott,Sergey Leikin,Elena Makareeva,Natalia V. Kuznetsova,Kenneth N. Rosenbaum,Cynthia J. Tifft,Dorothy I. Bulas,Chahira Kozma,Peter A. Smith,David R. Eyre,Joan C. Marini +14 more
TL;DR: The first five cases of a new recessive bone disorder resulting from null LEPRE1 alleles are presented; its phenotype overlaps with lethal/severe osteogenesis imperfecta but has distinctive features and a mutant allele from West Africa occurs in four of five cases.
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