HDAC inhibition improves autophagic and lysosomal function to prevent loss of subcutaneous fat in a mouse model of Cockayne syndrome

Science Translational Medicine
Marc MajoraJean Krutmann

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 csb m/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 hy...Continue Reading

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Citations

Aug 2, 2019·EMBO Molecular Medicine·Rebecca L McIntyreGeorges E Janssens
May 23, 2019·Frontiers in Cellular Neuroscience·Astrid S Pfister
Jul 1, 2020·International Journal of Molecular Sciences·Ekaterina ProshkinaAlexey Moskalev
Aug 17, 2019·Frontiers in Cell and Developmental Biology·Leopold EckhartFlorian Gruber
May 27, 2020·Genetics and Molecular Biology·Alexandre Teixeira VessoniCamila Carrião Machado Garcia
May 1, 2021·International Journal of Molecular Sciences·Ai-Young Lee
Aug 17, 2021·Frontiers in Oncology·Rihan HaiGang Yin
Nov 16, 2021·The British Journal of Dermatology·D Bergamaschi

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