Abstract
The Hedgehog pathway, critical to vertebrate development, is organized in primary cilia. Activation of signaling causes the Hedgehog receptor Ptch1 to exit cilia, allowing a second receptor, Smo, to accumulate in cilia and activate the downstream steps of the pathway. Mechanisms regulating the dynamics of these receptors are unknown, but the ubiquitination of Smo regulates its interaction with the intraflagellar transport system to control ciliary levels. A focused screen of ubiquitin-related genes identified nine required for maintaining low ciliary Smo at the basal state. These included cytoplasmic E3s (Arih2, Mgrn1, and Maea), a ciliary localized E3 (Wwp1), a ciliary localized E2 (Ube2l3), a deubiquitinase (Bap1), and three adaptors (Kctd5, Skp1a, and Skp2). The ciliary E3, Wwp1, binds Ptch1 and localizes to cilia at the basal state. Activation of signaling removes both Ptch1 and Wwp1 from cilia, thus providing an elegant mechanism for Ptch1 to regulate ciliary Smo levels.
© 2021 Lv et al.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Biological Transport / genetics
-
Cell Adhesion Molecules / genetics
-
Cell Adhesion Molecules / metabolism
-
Cell Line, Transformed
-
Cilia / metabolism*
-
Cilia / ultrastructure
-
Cytoskeletal Proteins / genetics
-
Cytoskeletal Proteins / metabolism
-
Fibroblasts / metabolism*
-
Fibroblasts / ultrastructure
-
Gene Expression Regulation*
-
HEK293 Cells
-
Humans
-
Mice
-
Patched-1 Receptor / genetics
-
Patched-1 Receptor / metabolism
-
Potassium Channels / genetics
-
Potassium Channels / metabolism
-
Protein Transport
-
S-Phase Kinase-Associated Proteins / genetics
-
S-Phase Kinase-Associated Proteins / metabolism
-
Signal Transduction
-
Smoothened Receptor / genetics*
-
Smoothened Receptor / metabolism
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / metabolism
-
Ubiquitin Thiolesterase / genetics
-
Ubiquitin Thiolesterase / metabolism
-
Ubiquitin-Conjugating Enzymes / genetics
-
Ubiquitin-Conjugating Enzymes / metabolism
-
Ubiquitin-Protein Ligases / genetics*
-
Ubiquitin-Protein Ligases / metabolism
-
Ubiquitination
Substances
-
BAP1 protein, mouse
-
Cell Adhesion Molecules
-
Cytoskeletal Proteins
-
Patched-1 Receptor
-
Potassium Channels
-
Ptch1 protein, mouse
-
S-Phase Kinase-Associated Proteins
-
SKP1A protein, mouse
-
Smo protein, mouse
-
Smoothened Receptor
-
Tumor Suppressor Proteins
-
erythroblast macrophage protein, mouse
-
Ube2l3 protein, mouse
-
Ubiquitin-Conjugating Enzymes
-
WWP1 protein, mouse
-
Arih2 protein, mouse
-
Mgrn1 protein, mouse
-
Ubiquitin-Protein Ligases
-
Ubiquitin Thiolesterase