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

Kazuo Noda, Kaori Kitagawa, Takao Miki, Masahito Horiguchi, Tomoya O. Akama, Takako Taniguchi, Hisaaki Taniguchi, Kazuaki Takahashi, Yasumitsu Ogra, Robert P. Mecham, Masahiko Terajima, Mitsuo Yamauchi, Tomoyuki Nakamura

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28 Scopus citations


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.

Original languageEnglish
Article numberabc1404
JournalScience Advances
Issue number48
StatePublished - Nov 25 2020


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