A matricellular protein fibulin-4 is essential for the activation of lysyl oxidase

• Published in: Science advances Vol. 6; no. 48
• Main Authors: Noda, Kazuo, Kitagawa, Kaori, Miki, Takao, Horiguchi, Masahito, Akama, Tomoya O, Taniguchi, Takako, Taniguchi, Hisaaki, Takahashi, Kazuaki, Ogra, Yasumitsu, Mecham, Robert P, Terajima, Masahiko, Yamauchi, Mitsuo, Nakamura, Tomoyuki
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.11.2020
• Subjects: Animals; Biochemistry; Collagen - metabolism; Copper; Elastin - metabolism; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Mice; Protein-Lysine 6-Oxidase - genetics; Protein-Lysine 6-Oxidase - metabolism; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abc1404

Fibulin-4 is a matricellular protein required for extracellular matrix (ECM) assembly. Mice deficient in fibulin-4 ( ) 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 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.