ABSTRACT
The palmoplantar epidermis is a specialized area of the skin that undergoes high levels of mechanical stress. The palmoplantar keratinization and esophageal cancer syndrome, tylosis with esophageal cancer, is linked to mutations in RHBDF2 encoding the proteolytically inactive rhomboid protein, iRhom2. Subsequently, iRhom2 was found to affect palmoplantar thickening to modulate the stress keratin response and to mediate context-dependent stress pathways by p63. iRhom2 is also a direct regulator of the sheddase, ADAM17, and the antiviral adaptor protein, stimulator of IFN genes. In this perspective, the pleiotropic functions of iRhom2 are discussed with respect to the skin, inflammation, and the antiviral response.
Subject(s)
Dermatitis/immunology , Epidermis/pathology , Esophageal Neoplasms/genetics , Intracellular Signaling Peptides and Proteins/genetics , Keratoderma, Palmoplantar/genetics , Skin Diseases, Viral/immunology , ADAM17 Protein/metabolism , Animals , Carrier Proteins/genetics , Carrier Proteins/metabolism , Dermatitis/genetics , Disease Models, Animal , Epidermis/immunology , Esophageal Neoplasms/immunology , Esophageal Neoplasms/pathology , Foot , Gene Expression Regulation/immunology , Hand , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Keratinocytes/immunology , Keratinocytes/metabolism , Keratins/metabolism , Keratoderma, Palmoplantar/immunology , Keratoderma, Palmoplantar/pathology , Mice , Mice, Knockout , Mutation , Signal Transduction/genetics , Signal Transduction/immunology , Skin Diseases, Viral/genetics , Skin Diseases, Viral/virology , Transcription Factors/metabolism , Tumor Suppressor Proteins/metabolismABSTRACT
We demonstrate that a Drosophila Golgi protein, Gorab, is present not only in the trans-Golgi but also in the centriole cartwheel where, complexed to Sas6, it is required for centriole duplication. In addition to centriole defects, flies lacking Gorab are uncoordinated due to defects in sensory cilia, which lose their nine-fold symmetry. We demonstrate the separation of centriole and Golgi functions of Drosophila Gorab in two ways: first, we have created Gorab variants that are unable to localize to trans-Golgi but can still rescue the centriole and cilia defects of gorab null flies; second, we show that expression of C-terminally tagged Gorab disrupts Golgi functions in cytokinesis of male meiosis, a dominant phenotype overcome by mutations preventing Golgi targeting. Our findings suggest that during animal evolution, a Golgi protein has arisen with a second, apparently independent, role in centriole duplication.
Subject(s)
Centrioles/genetics , Golgi Apparatus/genetics , Vesicular Transport Proteins/genetics , Animals , Animals, Genetically Modified/genetics , Cell Cycle/genetics , Cell Cycle Proteins/genetics , Cilia/genetics , Drosophila/genetics , Drosophila Proteins/genetics , Female , Humans , Male , Microtubule-Associated Proteins/genetics , Protein Serine-Threonine Kinases/geneticsABSTRACT
Centrioles are required to assemble centrosomes for cell division and cilia for motility and signalling. New centrioles assemble perpendicularly to pre-existing ones in G1-S and elongate throughout S and G2. Fully elongated daughter centrioles are converted into centrosomes during mitosis to be able to duplicate and organize pericentriolar material in the next cell cycle. Here we show that centriole-to-centrosome conversion requires sequential loading of Cep135, Ana1 (Cep295) and Asterless (Cep152) onto daughter centrioles during mitotic progression in both Drosophila melanogaster and human. This generates a molecular network spanning from the inner- to outermost parts of the centriole. Ana1 forms a molecular strut within the network, and its essential role can be substituted by an engineered fragment providing an alternative linkage between Asterless and Cep135. This conserved architectural framework is essential for loading Asterless or Cep152, the partner of the master regulator of centriole duplication, Plk4. Our study thus uncovers the molecular basis for centriole-to-centrosome conversion that renders daughter centrioles competent for motherhood.
