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Identification of CDC42 Effectors Operating in FGD1-Dependent Trafficking at the Golgi

Loss of function mutations in the FGD1 gene cause a rare X-linked disease, faciogenital dysplasia (FGDY, also known as Aarskog-Skott syndrome), which is associated with bone and urogenital abnormalities. The FGD1 gene encodes à CDC42-specific guanine nucleotide exchange factor. The mutations are fre...

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Detalles Bibliográficos
Autores principales: Egorov, Mikhail, Polishchuk, Roman
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369352/
https://www.ncbi.nlm.nih.gov/pubmed/30778386
http://dx.doi.org/10.3389/fcell.2019.00007
Descripción
Sumario:Loss of function mutations in the FGD1 gene cause a rare X-linked disease, faciogenital dysplasia (FGDY, also known as Aarskog-Skott syndrome), which is associated with bone and urogenital abnormalities. The FGD1 gene encodes à CDC42-specific guanine nucleotide exchange factor. The mutations are frequently located in the DH module of FGD1 preventing its transformation to the active form. We previously reported that Golgi-associated FGD1 regulates post-Golgi transport of some conventional and bone-specific proteins in a CDC42-dependent manner. However, the downstream targets of FGD1/CDC42 signaling that operate to support transport from the Golgi remain elusive. Here, we demonstrate that Golgi-localized CDC42 effectors might be involved in FGD1-mediated post-Golgi transport, probably through coordination of Golgi membrane and cytoskeleton dynamics. Overexpression of effector-specific CDC42 mutants (exhibiting preferential affinities for PAK1, IQGAP1, N-WASP, or PAR6) only partially rescue membrane trafficking in FGD1-deficient cells, indicating that the orchestrated activities of several downstream targets of CDC42 are required to support FGD1-mediated export from the Golgi. Our findings provide new insights into understanding the molecular mechanisms behind FGD1/CDC42-dependent transport events and uncover new targets whose potential might be explored for correction of membrane trafficking in FGDY.