Cockayne syndrome (CS), a hereditary form of premature aging predominantly caused by mutations in the 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,, and mice, we show that CSB promotes acetylation of α-tubulin and thereby regulates autophagy. At the organ level, chronic exposure of 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 mice. HDAC inhibition may thus represent a therapeutic option for CS.

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The hereditary progeria CS is predominantly caused by mutations in the csb gene. CS has originally been classified as a DNA repair disorder, but we have previously shown that also autophagy is dysfunctional in CS and that this autophagic block may be overcome by treatment with the pan HDAC inhibitor SAHA. Importantly, SAHA, which is a registered drug, was capable of rescuing the skin phenotype of UV-irradiated CSB-deficient mice. In the present study we therefore asked how SAHA treatment can improve autophagy in CS. One essential step in autophagy is acetylation of a-tubulin which is promotes effective fusion of autophagosomes with lysosomes. We now report that in CS models from three different species autophagic dysfunction was associated with decreased acetyl-a-tubulin levels, and that SAHA treatment improved both a-tubulin acetylation and autophagy. Further analysis in human fibroblasts showed that upon exposure to UV stress, wildtype, but also mutant CSB protein was recruited to the centrosome where it co-localized with dynein and HDAC6. This indicates that lack of a-tubulin acetylation in CS is not due to deficient CSB translocation, but most likely results from the disturbed interaction of CSB with HDAC6, dynein and/or yet to be defined centrosomal proteins. Accordingly, inhibition of HDAC6 was sufficient to enhance autophagic flux in CSB-deficient fibroblasts, and this effect critically depended on tubulin integrity and dynein function. Our results suggest that (i) the CSB protein has an important function outside of the nucleus, where it regulates autophagy by interacting with centrosomal proteins to acetylate a-tubulin and that (ii) SAHA treatment works in CS by overcoming deficient a-tubulin acetylation.

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