A matricellular protein fibulin-4 is essential for the activation of lysyl oxidase.
Kazuo NodaKaori KitagawaTakao MikiMasahito HoriguchiTomoya O AkamaTakako TaniguchiHisaaki TaniguchiKazuaki TakahashiYasumitsu OgraRobert P MechamMasahiko TerajimaMitsuo YamauchiTomoyuki NakamuraPublished in: Science advances (2020)
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.
Keyphrases
- extracellular matrix
- wild type
- induced apoptosis
- low density lipoprotein
- cell cycle arrest
- endoplasmic reticulum stress
- amino acid
- protein protein
- type diabetes
- metabolic syndrome
- heart failure
- coronary artery
- skeletal muscle
- small molecule
- signaling pathway
- adipose tissue
- tissue engineering
- wound healing
- gestational age
- aortic dissection
- pregnancy outcomes
- resting state