title: The C-terminal domain (CTD) in linker histones antagonizes anti-apoptotic proteins to modulate apoptotic outcomes at the mitochondrion.
abstract: 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-Cβ1 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.
authors: 1] National Centre for Biological Sciences, Bangalore, India [2] Department of Biotechnology, Mysore University, Mysore, India.
authors: M
authors: M
authors: Garg
authors: National Centre for Biological Sciences, Bangalore, India.
authors: N
authors: N
authors: Ramdas
authors: National Centre for Biological Sciences, Bangalore, India.
authors: M
authors: M
authors: Vijayalakshmi
authors: 1] National Centre for Biological Sciences, Bangalore, India [2] Mechanobiology Institute, National University of Singapore, Singapore.
authors: G V
authors: GV
authors: Shivashankar
authors: National Centre for Biological Sciences, Bangalore, India.
authors: A
authors: A
authors: Sarin
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; C569262:H1-1 protein, human; D006657:Histones; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; C579054:PRKCB protein, human; D064546:Protein Kinase C beta