Cellular stress due to impairment of collagen prolyl hydroxylation complex is rescued by the chaperone 4-phenylbutyrate

被引:39
作者
Besio, Roberta [1 ]
Garibaldi, Nadia [1 ,2 ]
Leoni, Laura [1 ]
Cipolla, Lina [3 ]
Sabbioneda, Simone [3 ]
Biggiogera, Marco [4 ]
Mottes, Monica [5 ]
Aglan, Mona [6 ]
Otaify, Ghada A. [6 ]
Temtamy, Samia A. [6 ]
Rossi, Antonio [1 ]
Forlino, Antonella [1 ]
机构
[1] Univ Pavia, Biochem Unit, Dept Mol Med, I-27100 Pavia, Italy
[2] IUSS, I-27100 Pavia, Italy
[3] CNR, Ist Genet Mol, I-27100 Pavia, Italy
[4] Univ Pavia, Dept Biol & Biotechnol, I-27100 Pavia, Italy
[5] Univ Verona, Dept Neurosci Biomed & Movement, I-37134 Verona, Italy
[6] Natl Res Ctr, Ctr Excellence Human Genet, Dept Clin Genet, Human Genet & Genome Res Div, Cairo 12622, Egypt
基金
欧洲研究理事会;
关键词
Osteogenesis imperfecta; Endoplasmic reticulum stress; Chemical chaperone; Unfolded protein response; 4-PBA; RECESSIVE OSTEOGENESIS IMPERFECTA; CYCLOPHILIN-B; MOUSE MODEL; 3-HYDROXYLATION; MUTATIONS; PHENOTYPE; PROTEIN; LETHAL; DEFICIENCY; AUTOPHAGY;
D O I
10.1242/dmm.038521
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
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页数:14
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