Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis.
Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis.
复制标题
DOI：
10.1038/ncomms12111
复制
发表时间：
2016-07-20
影响因子：
16.6
通讯作者：
Gissen P
中科院分区：
文献类型：
--
作者：
Banushi B;Forneris F;Straatman-Iwanowska A;Strange A;Lyne AM;Rogerson C;Burden JJ;Heywood WE;Hanley J;Doykov I;Straatman KR;Smith H;Bem D;Kriston-Vizi J;Ariceta G;Risteli M;Wang C;Ardill RE;Zaniew M;Latka-Grot J;Waddington SN;Howe SJ;Ferraro F;Gjinovci A;Lawrence S;Marsh M;Girolami M;Bozec L;Mills K;Gissen P
翻译后修饰对于胶原前体分子（前胶原）获得最终形状和功能是必需的。然而，发生在内质网和高尔基体外的胶原蛋白修饰的机制和贡献尚不清楚。我们发现，VIPAR及其伴侣蛋白调节赖氨酰羟化酶3（LH3，也称为PLOD3）分选到新鉴定的高尔基体后胶原IV载体中，并且VIPAR依赖性分选对于多种胶原类型中赖氨酸的修饰是必不可少的。从VIPAR和VPS33 B缺陷引起的常染色体隐性多系统疾病关节弯曲、肾功能不全和胆汁淤积综合征的患者和小鼠模型的细胞和组织中鉴定结构和功能胶原异常证实了我们的发现。因此，调节后高尔基体LH 3运输是胶原蛋白稳态和多个器官和组织的发育和功能所必需的。 胶原纤维交联和稳定化需要LH3对前胶原前体进行赖氨酸羟基化。在这里，作者表明，运输蛋白VIPAR是LH3正确分选到高尔基体后胶原载体和正确的胶原修饰和结构所必需的。
Post-translational modifications are necessary for collagen precursor molecules (procollagens) to acquire final shape and function. However, the mechanism and contribution of collagen modifications that occur outside the endoplasmic reticulum and Golgi are not understood. We discovered that VIPAR, with its partner proteins, regulate sorting of lysyl hydroxylase 3 (LH3, also known as PLOD3) into newly identified post-Golgi collagen IV carriers and that VIPAR-dependent sorting is essential for modification of lysines in multiple collagen types. Identification of structural and functional collagen abnormalities in cells and tissues from patients and murine models of the autosomal recessive multisystem disorder Arthrogryposis, Renal dysfunction and Cholestasis syndrome caused by VIPAR and VPS33B deficiencies confirmed our findings. Thus, regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis and for the development and function of multiple organs and tissues. Lysine hydroxylation of procollagen precursors by LH3 is required for collagen fibril crosslinking and stabilization. Here the authors show that the trafficking protein VIPAR is required for correct sorting of LH3 into post-Golgi collagen carriers and for correct collagen modification and structure.