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

Sci Adv. 2020 Nov 25;6(48):eabc1404. doi: 10.1126/sciadv.abc1404. Print 2020 Nov.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Collagen / metabolism
  • Copper
  • Elastin* / metabolism
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Mice
  • Protein-Lysine 6-Oxidase* / genetics
  • Protein-Lysine 6-Oxidase* / metabolism


  • Extracellular Matrix Proteins
  • fibulin-4, mouse
  • Copper
  • Collagen
  • Elastin
  • Protein-Lysine 6-Oxidase