Secreted
metalloproteases have diverse roles in the formation, remodeling, and the destruction of extracellular matrix. Recessive mutations in the secreted
metalloprotease ADAMTS17 cause
ectopia lentis and short stature in humans with
Weill-Marchesani-like syndrome and
primary open angle glaucoma and
ectopia lentis in dogs. Little is known about this
protease or its connection to
fibrillin microfibrils, whose major component,
fibrillin-1, is genetically associated with
ectopia lentis and alterations in height.
Fibrillin microfibrils form the ocular zonule and are present in the drainage apparatus of the eye. We show that recombinant ADAMTS17 has unique characteristics and an unusual life cycle. It undergoes rapid autocatalytic processing in trans after its secretion from cells. Secretion of ADAMTS17 requires O-fucosylation and its autocatalytic activity does not depend on propeptide processing by
furin. ADAMTS17 binds recombinant
fibrillin-2 but not
fibrillin-1 and does not cleave either. It colocalizes to
fibrillin-1 containing microfibrils in cultured fibroblasts and suppresses
fibrillin-2 (FBN2) incorporation in microfibrils, in part by transcriptional downregulation of Fbn2
mRNA expression.
RNA in situ hybridization detected Adamts17 expression in specific structures in the eye, skeleton and other organs, where it may regulate the
fibrillin isoform composition of microfibrils.