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The deacetylase HDAC6 is an essential component of stress granules and plays a critical role in the cellular response to stress

Kwon, So Hee. The deacetylase HDAC6 is an essential component of stress granules and plays a critical role in the cellular response to stress. 2007, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_7874

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Abstract

The reversible acetylation of histones has a critical role in transcriptional regulation.
Likewise reversible acetylation of non-histones proteins is also important for other
cellular processes. Acetylation and deacetylation of histones and other proteins are
catalyzed by opposing histone acetyl transferases (HATs) and deacetylases (HDACs)
respectively. Among three classes of histone deacetylases, HDAC6 is a very unique class
II HDAC enzyme which possesses two independent deacetylase domains and a Zn-UBP
ubiquitin binding domain at the C-terminus. HDAC6 has been shown to interact with
nuclear proteins as well as cytoplasmic proteins such as tubulin and HSP90. However, the
physiological function of HDAC6 is not fully understood yet. Therefore, to further define
the cellular function of HDAC6, an identification of novel interacting proteins has been
undertaken.
The first section of this thesis describes the identification of one novel HDAC6
interacting protein and the role of HDAC6 in stress granule (SG) formation in response to
environmental stress. First of all, we identified new HDAC6 interacting proteins using
proteomic affinity trap approach. Here, we focused that HDAC6 interacts and colocalizes
with a previously identified stress granule component, G3BP (RasGAP
associated endoribonuclease) in vitro and in vivo. We first discovered that HDAC6 is a
stable and critical component of stress granules. Further experimental data suggested that
HDAC6 can regulate the assembly of SGs via recruiting SG components to the
microtubule system. Because of this HDAC6 may have an impact on various processes
involoving RNA metabolism and we provide initial evidence that the miRNA pathway is
indeed influenced by HDAC6 function.
The second section of this thesis examines the role of HDAC6 in response to various
stresses. The involvement of HDAC6, a multi-functional cytoplasmic deacetylase, in
processes such as the clearance of cytotoxic aggregated misfolded proteins and the
deacetylation of HSP90 chaperone, has prompted us to investigate a role for HDAC6 in
cellular protection under stress condition. In hypoxia, HDAC6 regulated stability of HIF-
1α by controlling its deacetylation. Indeed, loss of HDAC6 rendered cells more sensitive to programmed cell death. Moreover, depletion of HDAC6 affected the recovery of cells
from stress as well as the direct stress response, suggesting a significant role of HDAC6
as a cellular regulator of the stress response.
In addition, a number of other putative HDAC6 interactors are presented, which were
identified in the initial mass spectrometry screens. Several of these proteins encode
cytoplasmic factors that have a role in RNA metabolism, protein translation or in
cytoskeletal regulation. Therefore, it appears likely that at least some of these may turn
out to be relevant partners contributing to HDAC6 function.
Advisors:Matthias, Patrick D.
Committee Members:Meins, Frederick and Filipowicz, Witold
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:7874
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:177
Language:English
Identification Number:
Last Modified:23 Feb 2018 11:44
Deposited On:29 May 2009 08:43

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