The Deacetylase HDAC6 Regulates Aggresome Formation and Cell Viability in Response to Misfolded Protein Stress

Abstract

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.

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

“…Histone deacetylase 1 is key for tumour cell proliferation, and found to be upregulated in hormone refractory prostate cancer and breast cancer (Kawai et al, 2003;Halkidou et al, 2004). Although HDAC6 activity does not drive tumour cell proliferation, HDAC6 has been shown to regulate the response to misfolded protein stress and its inhibition has synergistic effects with Bortezomib, which is administered in relapsed multiple myeloma (Kawaguchi et al, 2003;Bali et al, 2005). We found potent synergy between R306465 and Bortezomib in a broad panel of haematological cell lines indicating that activity towards HDAC6 is not essential for Histone deacetylase inhibitors to work synergistically with Bortezomib.…”

Histone deacetylase inhibitors: molecular mechanisms of action

“…Disruption of the aggresome pathway HDAC6 is a component of the aggresome, a cellular structure that constitutes the major site of degradation for misfolded protein aggregates, both non-ubiquitinated and ubiquitinated misfolded proteins (Kawaguchi et al, 2003). Direction of misfolded proteins to aggresomes is essential for cell survival, since these proteins are susceptible to forming cytotoxic aggregates that can interfere with normal cell function.…”

“…HDAC6 has a high affinity for ubiquitin molecule (due to the presence of the ZnF-UBP or BUZ domain) and is involved in the transport of poly-ubiquitinated proteins (Boyault et al, 2006). HDAC6 deacetylase activity is important for transport of misfolded poly-ubiquitinated proteins to the aggresome, and loss of HDAC6 function makes cells more sensitive to misfolded protein stress induced by protease inhibitor and, as a consequence, cell death (Kawaguchi et al, 2003).…”

Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions

“…Aggresomes are pericentriolar cytoplasmic structures in which aggregated, polyubiquinated misfolded proteins can be sequestered (Johnston et al, 1998;Kopita, 2000;Garcia-Mata et al, 2002). Aggresome formation is microtubule dependent, with the involvement of histone deacytalase 6 (HDAC6) and motor proteins such as dynein (Johnston et al, 2002;Kawaguchi et al, 2003). The fact that TPMT*3A is targeted for accelerated proteasome-mediated degradation, with the involvement of molecular chaperones, raised the possibility that the two common polymorphisms in TPMT*3A might result in misfolding.…”