The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress.

By Y. Kawaguchi, Jeffrey J Kovacs, A. McLaurin, J. Vance, A. Ito, T. Yao. Cell, 2003

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The efficient clearance of cytotoxic misfolded protein aggregates is critical for cell survival. Misfolded protein aggregates are transported and removed from the cytoplasm by dynein motors via the microtubule network to a novel organelle termed the aggresome where they are processed. However, the means by which dynein motors recognize misfolded protein cargo, and the cellular factors that regulate aggresome formation, remain unknown. We have discovered that HDAC6, a microtubule-associated deacetylase, is a component of the aggresome. We demonstrate that HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes. Indeed, cells deficient in HDAC6 fail to clear misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins. These findings identify HDAC6 as a crucial player in the cellular management of misfolded protein-induced stress.

Subfields: Genetics, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/2c3ebb1d9bc9c9f32ac1b32ca20fb15e7d907f66

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Citations in the corpus

HDAC6 modulates cell motility by altering the acetylation level of cortactin. (2007, methodology): “To verify that HDAC6 mediates the deacetylation of cortactin, we used an established A549 cell line (HD6KD) in which HDAC6 expression is specifically knocked-down by a retrovirusmediated RNAi system (Kawaguchi et al., 2003).”
TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. (2010, background): “HDAC6 promotes the aggregation of polyubiquitinated proteins (252,253) and their autophagic degradation (254,255).”
A role for ubiquitin in selective autophagy. (2009, background): “It interacts directly with dynein motors, which are necessary for transportation of aggregated misfolded proteins to the MTOC (Kawaguchi et al., 2003).”
Cellular strategies for controlling protein aggregation (2010, background): “The transport of aggregated proteins to aggresomes is mediated by histone deacetylase 6 (HDAC6), which functions as an adaptor that binds polyubiquitin chains of substrates and the microtubule motor protein dynein, thereby mediating the transport of polyubiquitylated cargo along microtubules towards”
The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men (2008, background): “HDAC6 is a component of the aggresome, and treatment of cells with a proteasome inhibitor results in the accumulation of HDAC6 in polyubiquitin-containing aggresome”
Anticancer activities of histone deacetylase inhibitors (2006, background): “A different mechanistic explanation might relate to the essential role of HDAC6 in aggresome formatio”
Oxidative Stress in Aging Human Skin (2015, background): “While this may lead to an increase in the degradation of un-ubiquitinated oxidized proteins or smaller protein aggregates, ubiquitinated proteins begin to accumulate triggering different stress responses including lysosomal uptake [218,219].”
Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer (2006, background): “Cytoplasmic HDAC6 is crucial for the formation of aggresomes (organelles required for the efficient clearance of misfolded, toxic, cytoplasmic proteins), although in this case the role of protein acetylation remains unclea”