HDACs and Autophagy

Autophagy is regarded as a form of programmed cell death distinct from apoptosis that involves the degradation of nonfolded proteins, aberrant protein aggregates, and damaged cell components via the lysosomal machinery. Abnormal autophagy is believed to have an important role in tumor development (Mathew et al. 2007). HDACs, especially SIRT1 and HDAC6, are involved in the regulation of autophagy.

Sirtl has been found to promote autophagy through its deacetylase activity upon starvation. It forms a molecular complex with several essential components of the autophagy machinery, including autophagy proteins (Atg)5, Atg7, and Atg8, and it directly deacetylates these components in an NAD-dependent fashion in vitro. Lack of Sirtl leads to markedly elevated protein acetylation in both cultured cells and embryonic and neonatal tissues. Moreover, Sirtl mice partially resemble Atg5_/~ mice, suggesting that Sirtl is an important regulator of autophagy (Lee et al. 2008). The SIRT1-PARP-1 axis plays a critical role in the regulation of cigarette smoke (CS)-induced autophagy in lung epithelial cells, fibroblasts, and macrophages as evidenced by the attenuation of CS-induced autophagy by the

SIRT1 activator resveratrol, and the opposite effect of the SIRT1 inhibitor sirtinol (Hwang et al. 2010). Moreover, increased autophagy is induced by CS in the lungs of Sirt1 deficient mice (Hwang et al. 2010). SIRT1 also regulates autophagy via a longevity factor network, which includes the FOXO and p53 pathways (Salminen and Kaarniranta 2009).

HDAC6 is a cytoplasmic HDAC involved in autophagy. Starvation-induced autophagy is usually considered to be a nonselective degradation process, distinct from quality-control (QC) autophagy in its substrate selectivity and machinery (Luzikov 1999). This selective degradation requires an intact microtubule cytoskel-eton and HDAC6 (Iwata et al. 2005), and acts as a compensatory degradation system when the ubiquitin proteasome system is impaired (Pandey et al. 2007). A recent study demonstrated that HDAC6 promotes selective autophagy through a cortactin-dependent, actin-remodeling machinery, which assembles an F-actin network that stimulates autophagosome-lysosome fusion and substrate degradation (Lee et al. 2010). Although it is clear that HDAC6 functions in the aggresome pathway and HDAC6 is capable of deacetylating both alpha-tubulin and cortactin (Hubbert et al. 2002; Zhang et al. 2007), whether QC autophagy involves a direct deacetylation of cortactin and tubulin by HDAC6 is not yet understood.

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