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

Megha Garg,Apurva Sarin,G V Shivashankar,Lakshmi R Perumalsamy

doi:10.1155/2014/674753

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.

Highlights

Cells divide and differentiate to acquire distinct cell fates in multicellular organisms
Tcells proliferate and differentiate in response to antigen, to generate lineage-committed effectors, the bulk of which die, marking termination of the immune response [14]. Key elements of this process can be recapitulated in vitro, permitting investigations into the molecular regulation of T-cell apoptosis [16,17,18, 20, 21]. Using this experimental system we show that cytokine withdrawal from T-effectors triggers apoptotic damage characterized by nuclear fragmentation and externalization of phosphatidylserine (PS) at the cell membrane (Figures 1(a) and 1(b))
Loss of mitochondrial integrity is another feature of cells undergoing apoptotic duress and is reflected in the spatial redistribution of the flavoprotein, AIF [22]

Summary

Introduction

Cells divide and differentiate to acquire distinct cell fates in multicellular organisms. The intrinsic pathway is activated by metabolic and genotoxic stressors and integrated at the mitochondrion, with members of the Bcl-2 family, which comprise both pro- and antiapoptotic members emerging as dominant regulators of these responses [1, 3, 4]. Cross talk between these two pathways is well documented. Cell-death pathways are variously deployed during development and in adult tissues as seen in the nervous, reproductive, and immune system where cells are overproduced and removed by apoptosis [5,6,7,8,9]. Mechanisms by which cells perceive changes in their microenvironment are not fully understood

Methods

Results

Discussion

Conclusion