Fibulin-4 is a matricellular protein required for extracellular matrix (ECM) assembly. Mice deficient in fibulin-4 (Fbln4^−/−) have disrupted collagen and elastin fibers and die shortly after birth from aortic and diaphragmatic rupture. The function of fibulin-4 in ECM assembly, however, remains elusive. Here, we show that fibulin-4 is required for the activity of lysyl oxidase (LOX), a copper-containing enzyme that catalyzes the covalent cross-linking of elastin and collagen. LOX produced by Fbln4^−/− cells had lower activity than LOX produced by wild-type cells due to the absence of lysine tyrosyl quinone (LTQ), a unique cofactor required for LOX activity. Our studies showed that fibulin-4 is required for copper ion transfer from the copper transporter ATP7A to LOX in the trans-Golgi network (TGN), which is a necessary step for LTQ formation. These results uncover a pivotal role for fibulin-4 in the activation of LOX and, hence, in ECM assembly.

Fibulin-4 是细胞外基质 (ECM) 组装所需的基质细胞蛋白。缺乏fibulin-4 ( Fbln4 ^-/- ) 的小鼠会破坏胶原蛋白和弹性蛋白纤维，并在出生后不久死于主动脉和膈肌破裂。然而，fibulin-4 在 ECM 组装中的功能仍然难以捉摸。在这里，我们表明 fibulin-4 是赖氨酰氧化酶 (LOX) 的活性所必需的，这是一种催化弹性蛋白和胶原蛋白共价交联的含铜酶。Fbln4产生的 LOX ^-/-由于缺乏 LOX 活性所需的独特辅因子赖氨酸酪氨酰醌 (LTQ)，因此细胞的活性低于野生型细胞产生的 LOX。我们的研究表明，在跨高尔基网络 (TGN) 中，铜离子从铜转运蛋白 ATP7A 转移到 LOX 需要 fibulin-4，这是 LTQ 形成的必要步骤。这些结果揭示了 fibulin-4 在激活 LOX 以及因此在 ECM 组装中的关键作用。