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Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis
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Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis
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Journal Article
Cleavage of the Meckel-Gruber syndrome protein TMEM67 by ADAMTS9 uncouples Wnt signaling and ciliogenesis
2025
Overview
TMEM67
mutations cause Meckel-Gruber syndrome and other related ciliopathies. TMEM67 is involved in both ciliary transition zone assembly, and non-canonical Wnt signaling mediated by its extracellular domain. How TMEM67 performs these two separate functions is not known. We identify a cleavage motif in the extracellular domain of TMEM67 cleaved by the extracellular matrix metalloproteinase ADAMTS9. This cleavage regulates the abundance of two functional forms: a C-terminal portion which localizes to the ciliary transition zone regulating ciliogenesis, and a non-cleaved form which regulates Wnt signaling. By characterizing three
TMEM67
ciliopathy patient variants within the cleavage motif utilizing mammalian cell culture and
C. elegans
, we show the cleavage motif is essential for cilia structure and function, highlighting its clinical significance. We generated a non-cleavable TMEM67 mouse model which develop severe ciliopathies phenocopying
Tmem67
-/-
mice, but in contrast, transduces normal Wnt signaling, substantiating the existence of two functional forms of TMEM67.
How Meckel-Gruber syndrome protein TMEM67 functions in ciliogenesis and Wnt signaling simultaneously is unknown. Here the authors show that TMEM67 is proteolytically cleaved by the matrix metalloproteinase ADAMTS9 generating two functional isoforms.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/95
/ 14/19
/ 14/28
/ 14/63
/ 38/1
/ 38/109
/ 64/110
/ 64/60
/ 82/80
/ ADAMTS9 Protein - metabolism
/ Animals
/ Caenorhabditis elegans - genetics
/ Caenorhabditis elegans - metabolism
/ Cilia
/ Ciliary Motility Disorders - genetics
/ Ciliary Motility Disorders - metabolism
/ Cleavage
/ Humanities and Social Sciences
/ Humans
/ Isoforms
/ Kidneys
/ Kinases
/ Membrane Proteins - chemistry
/ Membrane Proteins - genetics
/ Membrane Proteins - metabolism
/ Mice
/ Mutation
/ Neurodevelopmental disorders
/ Peptides
/ Polycystic Kidney Diseases - genetics
/ Polycystic Kidney Diseases - metabolism
/ Polycystic Kidney Diseases - pathology
/ Proteins
/ Retinitis Pigmentosa - genetics
/ Retinitis Pigmentosa - metabolism
/ Science
