Unusual life cycle and impact on microfibril assembly of ADAMTS17, a secreted metalloprotease mutated in genetic eye disease.
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.
Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA.
Dirk
D
Hubmacher
Department of Biochemistry and Cell Biology, 450 Life Sciences Building, Stony Brook University, Stony Brook, NY 11794-5215, USA.
Michael
M
Schneider
Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
Steven J
SJ
Berardinelli
Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
Hideyuki
H
Takeuchi
Mass Spectrometry Laboratory for Protein Sequencing, Lerner Research Institute, Cleveland Clinic, Cleveland, USA.
Belinda
B
Willard
Department of Anatomy and Cell Biology and Faculty of Dentistry, McGill University, Montreal, Quebec, H3A OC7, Canada.
Dieter P
DP
Reinhardt
Department of Biochemistry and Cell Biology, 450 Life Sciences Building, Stony Brook University, Stony Brook, NY 11794-5215, USA.|Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
Robert S
RS
Haltiwanger
Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA.
Suneel S
SS
Apte
D000071096:ADAMTS Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D000071838:Fibrillin-1 / Q000378:metabolism; D000071840:Fibrillin-2 / Q000378:metabolism; D005643:Fucose / Q000378:metabolism; D045683:Furin / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D020894:Microfibrils / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051381:Rats; D056846:Weill-Marchesani Syndrome / Q000235:genetics*
D000071838:Fibrillin-1; D000071840:Fibrillin-2; D005643:Fucose; D045683:Furin; D000071096:ADAMTS Proteins; C579149:ADAMTS17 protein, human