期刊
SCIENCE ADVANCES
卷 6, 期 48, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abc1404
关键词
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资金
- Funding Program for Next Generation World-Leading Researchers in Japan [LS120]
- Japan Society for the Promotion of Science [16 K15749, 18H02960, 26670147, 16H05145, 17 K19534, 19H03439]
- TAKEDA Science Foundation [2015148418]
- NIH [HL53325, HL105314]
- Grants-in-Aid for Scientific Research [18H02960, 16H05145, 19H03439, 26670147] Funding Source: KAKEN
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.
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