The C-terminal domain (CTD) in linker histones antagonizes anti-apoptotic proteins to modulate apoptotic outcomes at the mitochondrion

Garg, Manoj and Ramdas, N. and Vijayalakshmi, M. and Shivashankar, G. V. and Sarin, A. (2014) The C-terminal domain (CTD) in linker histones antagonizes anti-apoptotic proteins to modulate apoptotic outcomes at the mitochondrion. Cell Death and Disease, 5 (2). ISSN 2041-4889

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The loss of mitochondrial integrity as a consequence of apoptogenic complexes formed on the outer membrane constitutes a key step in controlling progression of apoptotic cascades. Here, we show that multiple members of the linker histone (LH) family of proteins modify apoptotic cascades initiated by the Bcl-2 protein Bak, and impart resistance to its endogenous antagonist Bcl-xL. Our experiments reveal apoptogenic capabilities equivalent to those documented for H1.2 in H1.1 and H1.3 isoforms. Deletion mutants of H1.2 and site-directed mutagenesis of H1.1 and H1.2 implicated the C-terminal domain in apoptogenic activity. In this context, disruption of protein kinase-C activity using chemical inhibitors, dominant-negative approaches and RNA interference coupled with site-directed modifications in H1.1, identified the protein kinase-Cb1 isoform as a repressor of H1.1/H1.3 apoptogenic activity. Finally, a H1.2 C-terminal tail recombinant attenuated Bcl-xl inhibition of Bak-induced apoptosis, suggesting that the C-terminal domain was necessary and sufficient for apoptogenic functions. Thus, integration with apoptotic intermediates (via C-terminal tail interactions) may constitute a more generalized function of LH isoforms in apoptotic cascades.

Item Type: Article
Uncontrolled Keywords: article, priority journal, enzyme activity, Humans, RNA interference, Time Factors, carboxy terminal sequence, apoptosis, Apoptosis, Signal Transduction, Mitochondria, mitochondrion, Mutation, protein bcl 2, HeLa Cells, Protein Kinase Inhibitors, bcl-2 Homologous Antagonist-Killer Protein, bcl-X Protein, HEK293 Cells, histone, histone modification, Histones, Mutagenesis, protein Bak, protein bcl xl, Protein Interaction Domains and Motifs, Protein Isoforms, protein kinase C, Protein Kinase C beta, RNA Interference, site directed mutagenesis, Site-Directed, Transfection
Subjects: B Life Science > Biotechnology
Divisions: Department of > Biotechnology
Depositing User: Arshiya Kousar Library Assistant
Date Deposited: 04 Sep 2019 09:47
Last Modified: 20 Jul 2022 05:51

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