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Sci Transl Med ; 10(456)2018 08 29.
Article in English | MEDLINE | ID: mdl-30158153

ABSTRACT

Cockayne syndrome (CS), a hereditary form of premature aging predominantly caused by mutations in the csb gene, affects multiple organs including skin where it manifests with hypersensitivity toward ultraviolet (UV) radiation and loss of subcutaneous fat. There is no curative treatment for CS, and its pathogenesis is only partially understood. Originally considered for its role in DNA repair, Cockayne syndrome group B (CSB) protein most likely serves additional functions. Using CSB-deficient human fibroblasts, Caenorhabditiselegans, and mice, we show that CSB promotes acetylation of α-tubulin and thereby regulates autophagy. At the organ level, chronic exposure of csbm/m mice to UVA radiation caused a severe skin phenotype with loss of subcutaneous fat, inflammation, and fibrosis. These changes in skin tissue were associated with an accumulation of autophagic/lysosomal proteins and reduced amounts of acetylated α-tubulin. At the cellular level, we found that CSB directly interacts with the histone deacetylase 6 (HDAC6) and the α-tubulin acetyltransferase MEC-17. Upon UVA irradiation, CSB is recruited to the centrosome where it colocalizes with dynein and HDAC6. Administration of the pan-HDAC inhibitor SAHA (suberoylanilide hydroxamic acid) enhanced α-tubulin acetylation, improved autophagic function in CSB-deficient models from all three species, and rescued the skin phenotype in csbm/m mice. HDAC inhibition may thus represent a therapeutic option for CS.


Subject(s)
Autophagy/drug effects , Cockayne Syndrome/pathology , Histone Deacetylase Inhibitors/pharmacology , Lysosomes/metabolism , Subcutaneous Fat/pathology , Acetylation , Animals , Autophagy/radiation effects , Autophagy-Related Proteins/metabolism , Caenorhabditis elegans/drug effects , Centrosome/drug effects , Centrosome/metabolism , Centrosome/radiation effects , DNA Helicases/deficiency , DNA Helicases/metabolism , DNA Repair Enzymes/deficiency , DNA Repair Enzymes/metabolism , Disease Models, Animal , Fibroblasts/drug effects , Fibroblasts/metabolism , Fibroblasts/pathology , Fibroblasts/radiation effects , Lysosomes/drug effects , Lysosomes/radiation effects , Mice , Phenotype , Poly-ADP-Ribose Binding Proteins/deficiency , Poly-ADP-Ribose Binding Proteins/metabolism , Skin/pathology , Skin/radiation effects , Subcutaneous Fat/drug effects , Subcutaneous Fat/radiation effects , Tubulin/metabolism , Ubiquitinated Proteins/metabolism , Ultraviolet Rays , Vorinostat/pharmacology
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