Differential HDAC1/2 network analysis reveals a role for prefoldin/CCT in HDAC1/2 complex assembly

Abstract

HDAC1 and HDAC2 are components of several corepressor complexes (NuRD, Sin3, CoREST and MiDAC) that regulate transcription by deacetylating histones resulting in a more compact chromatin environment. This limits access of transcriptional machinery to genes and silences transcription. While using an AP-MS approach to map HDAC1/2 protein interaction networks, we noticed that N-terminally tagged versions of HDAC1 and HDAC2 did not assemble into HDAC corepressor complexes as expected, but instead appeared to be stalled with components of the prefoldin-CCT chaperonin pathway. These N-terminally tagged HDACs were also catalytically inactive. In contrast to the N-terminally tagged HDACs, C-terminally tagged HDAC1 and HDAC2 captured complete histone deacetylase complexes and the purified proteins had deacetylation activity that could be inhibited by SAHA (Vorinostat), a Class I/II HDAC inhibitor. This tag-mediated reprogramming of the HDAC1/2 protein interaction network suggests a mechanism whereby HDAC1 is first loaded into the CCT complex by prefoldin to complete folding, and then assembled into active, functional HDAC complexes. Imaging revealed that the prefoldin subunit VBP1 colocalises with nuclear HDAC1, suggesting that delivery of HDAC1 to the CCT complex happens in the nucleus.

The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression program to control neurite outgrowth

“…MiDAC is conserved from nematodes to humans (Bantscheff, Hopf et al, 2011, Hao, Xu et al, 2011. In humans, MiDAC is composed of HDAC1/2, the scaffolding protein DNTTIP1, and the ELM2-SANT domain containing scaffolding protein ELMSAN1 (also known as MIDEAS) and/or the closely ELMSAN1-related proteins TRERF1 and ZNF541 (ZFP541 or SHIP in mice) ( Figure 1A) (Banks, Miah et al, 2018, Bantscheff et al, 2011, Choi, Han et al, 2008, Hao et al, 2011, Joshi, Greco et al, 2013. MiDAC constitutes a stoichiometric tetrameric complex that requires the N-terminal dimerization domain of DNTTIP1 for assembly.…”

The prefoldin complex stabilizes the von Hippel-Lindau protein against aggregation and degradation

“…In summary, in addition to key cytoskeletal proteins, we have shown for the first time to our knowledge that the oligohexameric prefoldin cochaperone complex regulates the stability of a tumor suppressor gene product. Recently, the prefoldin complex has been implicated in the folding of the Histone Deacetylase HDAC1 involved in tumorigenesis [ 59 ]. Therefore, a broader role of prefoldin complex in pathological processes through the regulation of key proteins folding should now be considered.…”

To Divide or Invade: A Look Behind the Scenes of the Proliferation-Invasion Interplay in the Caenorhabditis elegans Anchor Cell

“…Besides HDA-1, MEP-1 and the cytosolic chaperonin containing TCP-1 (CCT) complex act upstream of fos-1 and actin polarity pathways. Interestingly, in the germ cells MEP-1 interacts with the NuRD complex to maintain the somatic differentiation (Unhavaithaya et al, 2002 ), and also the CCT complex interacts with HDAC1 (Dekker et al, 2008 ; Banks et al, 2018 ). However, how these chromatin modifiers precisely act in the invading AC remains to be studied.…”