Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation.
Sc65-Null Mice Provide Evidence for a Novel Endoplasmic Reticulum Complex Regulating Collagen Lysyl Hydroxylation.
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DOI：
10.1371/journal.pgen.1006002
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发表时间：
2016-04
期刊：
影响因子：
4.5
通讯作者：
Morello R
中科院分区：
文献类型：
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作者：
Heard ME;Besio R;Weis M;Rai J;Hudson DM;Dimori M;Zimmerman SM;Kamykowski JA;Hogue WR;Swain FL;Burdine MS;Mackintosh SG;Tackett AJ;Suva LJ;Eyre DR;Morello R
胶原蛋白是细胞外基质的主要成分，其完整性对于结缔组织和器官功能至关重要。最近对隐性成骨不全症 (OI) 的研究强调了参与细胞内胶原蛋白翻译后修饰、折叠和运输的蛋白质的重要性。在这里，我们描述了 SC65（联会复合物 65，P3H4）（一种 Leprecan 家族成员）的关键作用，作为与脯氨酰 3-羟化酶 3 的内质网 (ER) 复合物的一部分。该复合物通过与酶和/或亲环蛋白 B 的相互作用潜在地影响赖氨酰羟化酶 1 的活性。小鼠中 Sc65 的缺失导致该复合物不稳定，改变了胶原蛋白赖氨酸羟基化和交联导致结缔组织缺陷，包括低骨量和皮肤脆性。这是内质网中脯氨酰羟化酶复合物在胶原合成过程中控制赖氨酰羟化酶活性的第一个迹象。纤维状胶原蛋白是结缔组织细胞外基质 (ECM) 的主要成分。其中，I型胶原蛋白是人体内最丰富的蛋白质，是骨、真皮、肌腱和韧带ECM的大量成分； I 型胶原蛋白还存在于其他器官的基质中，包括心脏、肺和肾，当失调时，它会显着导致病理性纤维化。 I 型和其他胶原蛋白分子具有三螺旋折叠要求，并在内质网 (ER) 和高尔基体中经历大量细胞内翻译后修饰。我们和其他人已经证明，特定胶原蛋白修饰的改变/丢失可能导致严重的先天性疾病，例如成骨不全症（OI）。在这里，我们使用多学科方法描述了 SC65 蛋白（联会复合体 65 或 P3H4）的功能研究，SC65 是 Leprecan 基因蛋白家族的一个尚未充分表征的成员。我们提供的证据表明，SC65 是与脯氨酰 3-羟化酶 3 (P3H3)、赖氨酰羟化酶 1 (LH1) 和潜在亲环蛋白 B (CYPB) 组成的 ER 复合物的关键组成部分。小鼠中 Sc65 的缺失会导致该复合物的不稳定、胶原蛋白赖氨酸羟基化的位点特异性减少以及结缔组织缺陷，包括骨质减少和皮肤脆弱。
Collagen is a major component of the extracellular matrix and its integrity is essential for connective tissue and organ function. The importance of proteins involved in intracellular collagen post-translational modification, folding and transport was recently highlighted from studies on recessive forms of osteogenesis imperfecta (OI). Here we describe the critical role of SC65 (Synaptonemal Complex 65, P3H4), a leprecan-family member, as part of an endoplasmic reticulum (ER) complex with prolyl 3-hydroxylase 3. This complex affects the activity of lysyl-hydroxylase 1 potentially through interactions with the enzyme and/or cyclophilin B. Loss of Sc65 in the mouse results in instability of this complex, altered collagen lysine hydroxylation and cross-linking leading to connective tissue defects that include low bone mass and skin fragility. This is the first indication of a prolyl-hydroxylase complex in the ER controlling lysyl-hydroxylase activity during collagen synthesis. Fibrillar collagens are major components of connective tissue extracellular matrix (ECM). Among them, type I collagen is the most abundant protein in the human body and a large constituent of bone, dermis, tendon and ligament ECMs; type I collagen is also present in the stroma of other organs including heart, lung and kidney where, when dysregulated, it significantly contributes to pathological fibrosis. Type I and other collagen molecules have triple-helical folding requirements and undergo numerous intracellular post-translational modifications in the endoplasmic reticulum (ER) and Golgi apparatus. We and others have shown that alterations/loss of specific collagen modifications can lead to severe congenital disease such as osteogenesis imperfecta (OI). Here, using a multidisciplinary approach, we describe functional studies of the SC65 protein (Synaptonemal Complex 65 or P3H4), a poorly characterized member of the Leprecan gene family of proteins. We provide evidence that SC65 is a critical component of an ER complex with prolyl 3-hydroxylase 3 (P3H3), lysyl-hydroxylase 1 (LH1), and potentially cyclophilin B (CYPB). Loss of Sc65 in the mouse results in instability of this complex, site-specific reduction in collagen lysine hydroxylation and connective tissue defects including osteopenia and skin fragility.