HDAC6 Regulates Mutant SOD1 Aggregation through Two SMIR Motifs and Tubulin Acetylation

Gál, József; Chen, Jing; Barnett, Kelly R.; Yang, Liuqing; Brumley, Erin; Zhu, Haining

doi:10.1074/jbc.m112.431957

Cited by 61 publications

(57 citation statements)

References 48 publications

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“…SIRT1 expression has been shown to be decreased in lungs of patients with COPD (54,55). Our data implicate SIRT1 as an HDAC6 deacetylase and suggest a model in which HDAC6 deacetylase activity is reduced by CS as a result of SIRT1 downregulation, resulting in acetylation and catalytic inhibition of HDAC6 (74). Interestingly, SIRT1 inhibition has been shown to enhance autophagy induced by CS in the lungs of Sirt1 +/-mice (75).…”

Section: Figure 10mentioning

confidence: 73%

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

et al. 2013

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Chronic obstructive pulmonary disease (COPD) involves aberrant airway inflammatory responses to cigarette smoke (CS) that are associated with epithelial cell dysfunction, cilia shortening, and mucociliary clearance disruption. Exposure to CS reduced cilia length and induced autophagy in vivo and in differentiated mouse tracheal epithelial cells (MTECs). Autophagy-impaired (Becn1 +/-or Map1lc3B -/-) mice and MTECs resisted CS-induced cilia shortening. Furthermore, CS increased the autophagic turnover of ciliary proteins, indicating that autophagy may regulate cilia homeostasis. We identified cytosolic deacetylase HDAC6 as a critical regulator of autophagy-mediated cilia shortening during CS exposure. Mice bearing an X chromosome deletion of Hdac6 (Hdac6 -/Y ) and MTECs from these mice had reduced autophagy and were protected from CS-induced cilia shortening. Autophagy-impaired Becn1 -/-, Map1lc3B -/-, and Hdac6 -/Y mice or mice injected with an HDAC6 inhibitor were protected from CS-induced mucociliary clearance (MCC) disruption. MCC was preserved in mice given the chemical chaperone 4-phenylbutyric acid, but was disrupted in mice lacking the transcription factor NRF2, suggesting that oxidative stress and altered proteostasis contribute to the disruption of MCC. Analysis of human COPD specimens revealed epigenetic deregulation of HDAC6 by hypomethylation and increased protein expression in the airways. We conclude that an autophagy-dependent pathway regulates cilia length during CS exposure and has potential as a therapeutic target for COPD.

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Section: Figure 10mentioning

confidence: 73%

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

et al. 2013

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“…This phenotype was associated with an increase of α-tubulin acetylation and retrograde transport of mutated proteins. Mutant SOD1 oligomers and small aggregates sequester and inactivate HDAC6, favoring tubulin acetylation and leading to the formation of large pathologic inclusions [131]. Thus, if ELP3 represents a strong candidate to design new activator-based therapies, then much effort must be made to understand the precise outcomes of tubulin acetylation.…”

Section: Alsmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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“…These proteins are substrates of histone deacetylase (HDAC), which is likely to be dysfunctional in ALS patients. Concordantly, another study found that ALS-mutant SOD1 is capable of modulating HDAC6 activity (Gal et al, 2013), suggesting that the mutant protein may increase acetylation, potentially conferring proteasomal resistance and aiding the aggregation.…”

Section: Pathophysiologymentioning

confidence: 95%