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XB-ART-59107
J Cell Sci January 1, 2022; 135 (9):
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Cilia-localized GID/CTLH ubiquitin ligase complex regulates protein homeostasis of sonic hedgehog signaling components.

Hantel F , Liu H , Fechtner L , Neuhaus H , Ding J , Arlt D , Walentek P , Villavicencio-Lorini P , Gerhardt C , Hollemann T , Pfirrmann T .


Abstract
Cilia are evolutionarily conserved organelles that orchestrate a variety of signal transduction pathways, such as sonic hedgehog (SHH) signaling, during embryonic development. Our recent studies have shown that loss of GID ubiquitin ligase function results in aberrant AMP-activated protein kinase (AMPK) activation and elongated primary cilia, which suggests a functional connection to cilia. Here, we reveal that the GID complex is an integral part of the cilium required for primary cilia-dependent signal transduction and the maintenance of ciliary protein homeostasis. We show that GID complex subunits localize to cilia in both Xenopus laevis and NIH3T3 cells. Furthermore, we report SHH signaling pathway defects that are independent of AMPK and mechanistic target of rapamycin (MTOR) activation. Despite correct localization of SHH signaling components at the primary cilium and functional GLI3 processing, we find a prominent reduction of some SHH signaling components in the cilium and a significant decrease in SHH target gene expression. Since our data reveal a critical function of the GID complex at the primary cilium, and because suppression of GID function in X. laevis results in ciliopathy-like phenotypes, we suggest that GID subunits are candidate genes for human ciliopathies that coincide with defects in SHH signal transduction.

PubMed ID: 35543155
Article link: J Cell Sci
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: actb armc8 atp1a1 gli1 gli2 gli3 map1lc3a mkln1 nkx2-1 odc1 pax6 ptch1 rmnd5a rps6 sag shh slc12a3 slc5a2 slc5a5 slc5a9 smo sox2 sufu tuba4b
GO keywords: AMP-activated protein kinase activity [+]
Antibodies: Actb Ab10 Armc8 Ab2 Gid8 Ab1 Gli1 Ab3 Gli2 Ab4 Gli3 Ab1 Gpr161 Ab1 Map1lc3b Ab1 Mkln1 Ab1 Prkaa1 Ab1 Prkaa1 Ab2 Ptch1 Ab3 Rmnd5a Ab2 Rps6 AB4 Rps6 Ab3 Rptor Ab1 Rptor Ab2 Sqstm1 Ab1 Sufu Ab1 Tsc2 Ab1 Tuba4a Ab25 Tuba4b Ab5 Tubg1 Ab4
Morpholinos: rmnd5a MO1

Disease Ontology terms: ciliopathy [+]
Phenotypes: Xla Wt + rmnd5a MO (Fig.6.E-F) [+]

Article Images: [+] show captions