4-PBA ameliorates cellular homeostasis in fibroblasts from osteogenesis imperfecta patients by enhancing autophagy and stimulating protein secretion.
4-PBA ameliorates cellular homeostasis in fibroblasts from osteogenesis imperfecta patients by enhancing autophagy and stimulating protein secretion.
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DOI：
10.1016/j.bbadis.2018.02.002
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Forlino A
中科院分区：
文献类型：
--
作者：
Besio R;Iula G;Garibaldi N;Cipolla L;Sabbioneda S;Biggiogera M;Marini JC;Rossi A;Forlino A
骨生成障碍（OI）的临床表型归因于细胞外基质中突变型I型胶原分子的显性负功能，通过改变其结构和功能。也有报道突变胶原蛋白的细胞内滞留，但其对细胞内稳态的影响特征较少。使用在α1（I）和α2（I）链中携带突变的OI患者成纤维细胞，我们证明保留的胶原分子主要通过真核翻译起始因子2 α激酶3（PERK）分支负责内质网（ER）扩大和未折叠蛋白反应（UPR）的激活。携带α1（I）突变的细胞上调自噬，而携带α2（I）突变的细胞仅偶尔激活自降解反应。尽管自噬活化以面对应激条件，但凋亡发生在所有突变成纤维细胞中。为了减少细胞应激，用FDA批准的化学伴侣4-苯基丁酸处理突变的成纤维细胞。由于其分子伴侣和组蛋白脱乙酰酶抑制剂的能力，该药物通过调节UPR激活来挽救细胞死亡。作为分子伴侣，它增加所有患者细胞中的一般细胞蛋白质分泌以及具有最多C末端突变的细胞中的胶原蛋白分泌。作为组蛋白去乙酰化酶抑制剂，其增强自噬基因Atg 5的表达，从而刺激自噬。这些结果表明，细胞对ER应激的反应可以是改善OI细胞稳态的相关靶点。保留的突变胶原激活未折叠蛋白反应途径。自噬在携带α1（I）突变的成纤维细胞中持续上调。自噬有时在携带α2（I）突变的成纤维细胞中上调。细胞凋亡发生在所有携带I型胶原突变的突变成纤维细胞中4-PBA通过调节UPR活化和活化自噬来挽救细胞死亡。
The clinical phenotype in osteogenesis imperfecta (OI) is attributed to the dominant negative function of mutant type I collagen molecules in the extracellular matrix, by altering its structure and function. Intracellular retention of mutant collagen has also been reported, but its effect on cellular homeostasis is less characterized. Using OI patient fibroblasts carrying mutations in the α1(I) and α2(I) chains we demonstrate that retained collagen molecules are responsible for endoplasmic reticulum (ER) enlargement and activation of the unfolded protein response (UPR) mainly through the eukaryotic translation initiation factor 2 alpha kinase 3 (PERK) branch. Cells carrying α1(I) mutations upregulate autophagy, while cells with α2(I) mutations only occasionally activate the autodegradative response. Despite the autophagy activation to face stress conditions, apoptosis occurs in all mutant fibroblasts. To reduce cellular stress, mutant fibroblasts were treated with the FDA-approved chemical chaperone 4-phenylbutyric acid. The drug rescues cell death by modulating UPR activation thanks to both its chaperone and histone deacetylase inhibitor abilities. As chaperone it increases general cellular protein secretion in all patients' cells as well as collagen secretion in cells with the most C-terminal mutation. As histone deacetylase inhibitor it enhances the expression of the autophagic gene Atg5 with a consequent stimulation of autophagy. These results demonstrate that the cellular response to ER stress can be a relevant target to ameliorate OI cell homeostasis. Retained mutant collagen activates the Unfolded Protein Response pathway. Autophagy is consistently upregulated in fibroblasts carrying α1(I) mutations. Autophagy is sometimes upregulated in fibroblasts carrying α2(I) mutations. Apoptosis occurs in all mutant fibroblasts carrying type I collagen mutations 4-PBA rescues cell death by modulating UPR activation and activating autophagy.
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影响因子：
3.5
作者：
Gioia R;Tonelli F;Ceppi I;Biggiogera M;Leikin S;Fisher S;Tenedini E;Yorgan TA;Schinke T;Tian K;Schwartz JM;Forte F;Wagener R;Villani S;Rossi A;Forlino A
通讯作者：
Forlino A
影响因子：
4.2
作者：
Fass, Daniel M.;Shah, Rishita;Ghosh, Balaram;Hennig, Krista;Norton, Stephanie;Zhao, Wen-Ning;Reis, Surya A.;Klein, Peter S.;Mazitschek, Ralph;Maglathlin, Rebecca L.;Lewis, Timothy A.;Haggarty, Stephen J.
通讯作者：
Haggarty, Stephen J.
DOI：
10.15252/embj.201489183
发表时间：
2015-06-03
期刊：
The EMBO journal
影响因子：
--
作者：
Carrara M;Prischi F;Nowak PR;Ali MM
通讯作者：
Ali MM
影响因子：
4.5
作者：
Cabral WA;Ishikawa M;Garten M;Makareeva EN;Sargent BM;Weis M;Barnes AM;Webb EA;Shaw NJ;Ala-Kokko L;Lacbawan FL;Högler W;Leikin S;Blank PS;Zimmerberg J;Eyre DR;Yamada Y;Marini JC
通讯作者：
Marini JC
影响因子：
3.5
作者：
Bianchi, Laura;Gagliardi, Assunta;Forlino, Antonella
通讯作者：
Forlino, Antonella