The Linker Histone H1.2 Is an Intermediate in the Apoptotic Response to Cytokine Deprivation in T-Effectors

Abstract

Tissue homeostasis is a dynamic process involving proliferation and the removal of redundant or damaged cells. This is exemplified in the coordinated deletion—triggered by limiting trophic factors/cytokines in the extracellular milieu—of differentiated T cells overproduced during the mammalian immune response. However, mechanisms by which extracellular cues are perceived and transduced as apoptotic triggers remain incompletely understood. T-effectors are dependent on cytokines for survival and undergo apoptosis following cytokine withdrawal. Here we report that leptomycin B (LMB), an inhibitor of nuclear export machinery, protected T-effectors from apoptosis implicating a nuclear intermediate in the apoptotic pathway. Evidence is presented that the linker histone H1.2 localizes to the cytoplasm, by a mechanism sensitive to regulation by LMB, to activate apoptotic signaling culminating in nuclear and mitochondrial damage in T-effectors in response to cytokine deprivation. H1.2 is detected in a complex with the proapoptotic mitochondrial resident Bak and its subcellular localization regulated by Jun-N-terminal kinase (JNK), an intermediate in the apoptotic cascade in T-effectors. These data suggest that metabolic stressors may impinge on H1.2 dynamics favoring its activity at the mitochondrion, thereby functioning as a molecular switch for T-effector apoptosis.

The RNA interactome of human telomerase RNA reveals a coding-independent role for a histone mRNA in telomere homeostasis

“…For example, H1.2 has been shown to repress p53-mediated transcriptional activation of target genes through – in part – a direct interaction with p53 ( Kim et al, 2008 ; Nishiyama et al, 2009 ), conferring an anti-apoptotic function upon DNA damage ( Nishiyama et al, 2009 ). In contrast, the release of H1.2 from chromatin in response to DNA double-strand breaks has been shown to lead to its translocation to the cytoplasm and to result in the activation of the intrinsic apoptotic pathway and increased cell death in a Bak-dependent manner ( Garg et al, 2014 ; Konishi et al, 2003 ). Chromatin compaction states, regulated by linker histone abundance, might also influence various fundamental cellular processes, including the DNA damage response ( Murga et al, 2007 ; Sulli et al, 2012 ) and transcription from heterochromatic repeat regions ( Izquierdo-Bouldstridge et al, 2017 ), potentially modulating telomere length homeostasis.…”

Extra-nuclear histones: origin, significance and perspectives

“…It has further been seen that the core histones, especially histone H3, were targeted to the mitochondria after their release from the nucleus [17]. Similarly, histone H1.2 (a H1 variant) was also reported to be localized in the mitochondria of squamous carcinoma cells [18] and effector T-cells [19].…”

“…A major fraction of the cytoplasmic histones has been detected in the mitochondria by several groups [15,17,[30][31][32][33]. Further, targeting of the cytoplasmic histones to the mitochondria brings about the destabilization of its outer membrane [17].…”

Modulation of chromatin function through linker histone H1 variants

“…Experimental data point out that histone H1 exerts a subtype‐specific impact both on the DNA binding (Orrego et al., ) and chromatin condensation (Clausell et al., ). Moreover, the individual histone H1 subtypes affect many important cellular processes, including apoptosis (Konishi et al., ; Garg et al., ), differentiation (Terme et al., ), cell cycle progression and proliferation (Stoldt et al., ; Happel et al., ). Such differential histone H1 effects likely result from the combined impact of numerous factors which set the specific patterns for histone H1 subtype functioning.…”