1. A matricellular protein fibulin-4 is essential for the activation of lysyl oxidase
- Author
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Kazuo Noda, Tomoyuki Nakamura, Tomoya O. Akama, Mitsuo Yamauchi, Masahito Horiguchi, Takao Miki, Kaori Kitagawa, Masahiko Terajima, Kazuaki Takahashi, Yasumitsu Ogra, Hisaaki Taniguchi, Robert P. Mecham, and Takako Taniguchi
- Subjects
Lysine ,ATP7A ,Lysyl oxidase ,Biochemistry ,Cofactor ,Extracellular matrix ,Protein-Lysine 6-Oxidase ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Animals ,Research Articles ,030304 developmental biology ,0303 health sciences ,Extracellular Matrix Proteins ,Multidisciplinary ,integumentary system ,biology ,Chemistry ,Matricellular protein ,SciAdv r-articles ,Fibulin ,Cell biology ,Elastin ,enzymes and coenzymes (carbohydrates) ,030220 oncology & carcinogenesis ,biology.protein ,Collagen ,Copper ,Research Article - Abstract
A secreted protein activates a major extracellular matrix cross-linking enzyme by promoting copper ion transfer in the Golgi., 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.
- Published
- 2020