The concept of intrinsic versus extrinsic apoptosis.

Regulated cell death is a vital and dynamic process in multicellular organisms that maintains tissue homeostasis and eliminates potentially dangerous cells. Apoptosis, one of the better-known forms of regulated cell death, is activated when cell-surface death receptors like Fas are engaged by their ligands (the extrinsic pathway) or when BCL-2-family pro-apoptotic proteins cause the permeabilization of the mitochondrial outer membrane (the intrinsic pathway). Both the intrinsic and extrinsic pathways of apoptosis lead to the activation of a family of proteases, the caspases, which are responsible for the final cell demise in the so-called execution phase of apoptosis. In this review, I will first discuss the most common types of regulated cell death on a morphological basis. I will then consider in detail the molecular pathways of intrinsic and extrinsic apoptosis, discussing how they are activated in response to specific stimuli and are sometimes overlapping. In-depth knowledge of the cellular mechanisms of apoptosis is becoming more and more important not only in the field of cellular and molecular biology but also for its translational potential in several pathologies, including neurodegeneration and cancer.

VDAC2 and the BCL-2 family of proteins.

The BCL-2 protein family govern whether a cell dies or survives by controlling mitochondrial apoptosis. As dysregulation of mitochondrial apoptosis is a common feature of cancer cells, targeting protein-protein interactions within the BCL-2 protein family is a key strategy to seize control of apoptosis and provide favourable outcomes for cancer patients. Non-BCL-2 family proteins are emerging as novel regulators of apoptosis and are potential drug targets. Voltage dependent anion channel 2 (VDAC2) can regulate apoptosis. However, it is unclear how this occurs at the molecular level, with conflicting evidence in the literature for its role in regulating the BCL-2 effector proteins, BAK and BAX. Notably, VDAC2 is required for efficient BAX-mediated apoptosis, but conversely inhibits BAK-mediated apoptosis. This review focuses on the role of VDAC2 in apoptosis, discussing the current knowledge of the interaction between VDAC2 and BCL-2 family proteins and the recent development of an apoptosis inhibitor that targets the VDAC2-BAK interaction.

Long noncoding RNA CEBPA-DT promotes cisplatin chemo-resistance through CEBPA/BCL2 mediated apoptosis in oral squamous cellular cancer.

Intrinsic or developing resistance to chemotherapy drugs including cisplatin (CDDP) remains the major limitation of cancer therapeutic efficacy in cancers. Recently, increasing evidence suggested that long noncoding RNAs (lncRNAs) play a critical role in various biological processes of tumors, and have been implicated in resistance to various drugs. However, the role of lncRNAs in cisplatin resistance is poorly understood. Here, we found that the expression of lncRNA CEBPA-DT/CEBPA/BCL2 was upregulated in cisplatin resistance OSCC cells (Cal27-CisR and HSC4-CisR) compared with their parental cells (Cal27 and HSC4). CEBPA-DT overexpression could upregulated both cytoplasmic and nuclear CEBPA expression. Down-regulation of CEBPA-DT enhances cisplatin sensitivity, facilitates cell apoptosis in cisplatin-resistant OSCC cells. In addition, we identified that CEBPA-DT regulates cisplatin chemosensitivity through CEBPA/BCL2-mediated cell apoptosis. Knockdown of CEBPA and BCL2 could alleviate the increasement of cisplatin resistance induced by CEBPA-DT overexpression. Our findings indicate that downregulation of lncRNA CEBPA-DT may be a potential therapy to overcome cisplatin resistance in OSCC.

A proteomic analysis of Bcl-2 regulation of cell cycle arrest: insight into the mechanisms.

B cell lymphoma 2 (Bcl-2) is an important antiapoptotic gene that plays a dual role in the maintenance of the dynamic balance between the survival and death of cancer cells. In our previous study, Bcl-2 was shown to delay the G0/G1 to S phase entry by regulating the mitochondrial metabolic pathways to produce lower levels of adenosine triphosphate (ATP) and reactive oxygen species (ROS). However, the detailed molecular mechanisms or pathways by which Bcl-2 regulates the cell cycle remain unknown. Here, we compared the effects of Bcl-2 overexpression with an empty vector control in the NIH3T3 cell line synchronized by serum starvation, and evaluated the effects using proteomic analysis. The effect of Bcl-2 on cell cycle regulation was detected by monitoring Bcl-2 and p27 expression. The result of subsequent proteomic analysis of Bcl-2 overexpressing cells identified 169 upregulated and 120 downregulated proteins with a 1.5-fold change. These differentially expressed proteins were enriched in a number of signaling pathways predominantly involving the ribosome and oxidative phosphorylation, according to the data of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. These results indicated that Bcl-2 potentially acts at the translation level to influence proteins or enzymes of the respiratory chain or in the ribosome, and thereby regulates the cell cycle. Additionally, differentially expressed proteins involved in oxidative phosphorylation were determined to account for most of the effects of Bcl-2 on the cell cycle mediated by the mitochondrial pathway investigated in our previous study. These results can provide assistance for additional in-depth studies on the regulation of the cell cycle by Bcl-2. The results of the proteomic analysis determined the mechanism of Bcl-2-dependent delay of the cell cycle progression. In summary, the results of this study provide a novel mechanistic basis for identifying the key proteins or pathways for designing and developing precisely targeted cancer drugs.

The Role of BCL-2 Proteins in the Development of Castration-resistant Prostate Cancer and Emerging Therapeutic Strategies.

The development of androgen resistance in advanced prostate cancer remains a challenging clinical problem. Because androgen deprivation therapy constitutes the backbone of first-line treatments for metastatic prostate cancer, the phenotypic switch from an androgen-dependent to an androgen-independent growth state limits the treatment options for these patients. This critical change from an androgen-dependent to an androgen-independent growth state can be regulated by the B-cell lymphoma gene 2 (BCL-2) family of apoptotic proteins. While the roles of BCL-2 protein family members in the carcinogenesis of prostate cancer have been well-studied, emerging data also delineates their modulation of disease progression to castration-resistant prostate cancer (CRPC). Over the past 2 decades, investigators have sought to describe the mechanisms that underpin this development at the molecular level, yet no recent literature has consolidated these findings in a dedicated review. As new classes of BCL-2 family inhibitors are finding indications for other cancer types, it is time to evaluate how such agents might find stable footing for the treatment of CRPC. Several trials to date have investigated BCL-2 inhibitors as therapeutic agents for CRPC. These therapies include selective BCL-2 inhibitors, pan-BCL-2 inhibitors, and novel inhibitors of MCL-1 and BCL-XL. This review details the research regarding the role of BCL-2 family members in the pathogenesis of prostate cancer and contextualizes these findings within the contemporary landscape of prostate cancer treatment.

Insight into Functional Membrane Proteins by Solution NMR: The Human Bcl-2 Protein-A Promising Cancer Drug Target.

Evasion from programmed cell death (apoptosis) is the main hallmark of cancer and a major cause of resistance to therapy. Many tumors simply ensure survival by over-expressing the cell-protecting (anti-apoptotic) Bcl-2 membrane protein involved in apoptotic regulation. However, the molecular mechanism by which Bcl-2 protein in its mitochondrial outer membrane location protects cells remains elusive due to the absence of structural insight; and current strategies to therapeutically interfere with these Bcl-2 sensitive cancers are limited. Here, we present an NMR-based approach to enable structural insight into Bcl-2 function; an approach also ideal as a fragment-based drug discovery platform for further identification and development of promising molecular Bcl-2 inhibitors. By using solution NMR spectroscopy on fully functional intact human Bcl-2 protein in a membrane-mimicking micellar environment, and constructs with specific functions remaining, we present a strategy for structure determination and specific drug screening of functional subunits of the Bcl-2 protein as targets. Using 19F NMR and a specific fragment library (Bionet) with fluorinated compounds we can successfully identify various binders and validate our strategy in the hunt for novel Bcl-2 selective cancer drug strategies to treat currently incurable Bcl-2 sensitive tumors.

Ze-Qi-Tang Formula Induces Granulocytic Myeloid-Derived Suppressor Cell Apoptosis via STAT3/S100A9/Bcl-2/Caspase-3 Signaling to Prolong the Survival of Mice with Orthotopic Lung Cancer.

Non-small-cell lung cancer (NSCLC) remains the most common malignancy with the highest morbidity and mortality worldwide. In our previous study, we found that a classic traditional Chinese medicine (TCM) formula Ze-Qi-Tang (ZQT), which has been used in the treatment of respiratory diseases for thousands of years, could directly inhibit the growth of human NSCLC cells via the p53 signaling pathway. In this study, we explored the immunomodulatory functions of ZQT. We found that ZQT significantly prolonged the survival of orthotopic lung cancer model mice by modulating the tumor microenvironment (TME). ZQT remarkably reduced the number of MDSCs (especially G-MDSCs) and inhibited their immunosuppressive activity by inducing apoptosis in these cells via the STAT3/S100A9/Bcl-2/caspase-3 signaling pathway. When G-MDSCs were depleted, the survival promotion effect of ZQT and its inhibitory effect on lung luminescence signal disappeared in tumor-bearing mice. This is the first study to illustrate the immunomodulatory effect of ZQT in NSCLC and the underlying molecular mechanism.

Mitochondrial Homeostasis Mediates Lipotoxicity in the Failing Myocardium.

Heart failure remains the most common cause of death in the industrialized world. In spite of new therapeutic interventions that are constantly being developed, it is still not possible to completely protect against heart failure development and progression. This shows how much more research is necessary to understand the underlying mechanisms of this process. In this review, we give a detailed overview of the contribution of impaired mitochondrial dynamics and energy homeostasis during heart failure progression. In particular, we focus on the regulation of fatty acid metabolism and the effects of fatty acid accumulation on mitochondrial structural and functional homeostasis.

Can the interplay between autophagy and apoptosis be targeted as a novel therapy for Parkinson's disease?

Development of efficacious treatments for Parkinson's disease (PD) demands an improved understanding of mechanisms underlying neurodegeneration. Two cellular death pathways postulated to play key roles in PD are autophagy and apoptosis. Molecular overlap between these pathways was investigated through identifying studies that used therapeutic compounds to alter expression of specific molecular components of the pathways. Bcl-2 was identified as an important protein with the ability to suppress autophagy and apoptosis through inhibiting Beclin-1 and Bax, respectively. Involvement of c-Jun N-terminal kinases (JNK) and p38, was evident in the activation of apoptosis through increasing the Bax/Bcl-2 ratio. JNK-mediated phosphorylation also suppresses the inhibiting functions of Bcl-2, indicating an ability to induce not only apoptosis but also autophagy. Additionally, a p38-mediated increase in heme oxygenase-1 expression inhibits apoptosis. Moreover, besides inhibiting mammalian target of rapamycin, Akt is associated with decreased Bax expression, thereby acting as both an autophagy inducer and apoptosis inhibitor. Ultimately, manipulation of molecular components involved in autophagy and apoptosis regulation could be targeted as possible therapies for PD.

Combination of Huanglian Jiedu Decoction and erlotinib delays growth and improves sensitivity of EGFR­mutated NSCLC cells in vitro and in vivo via STAT3/Bcl­2 signaling.

Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is widely used in the treatment of non­small cell lung cancer (NSCLC). However, erlotinib resistance leads to high mortality in patients with NSCLC, while the activation of STAT3 is closely related to erlotinib resistance. Studies have shown that the main components of Huanglian Jiedu Decoction (HJD) have antitumor effects. Therefore, the anticancer effect of HJD combined with erlotinib on NSCLC cells was investigated. The NSCLC HCC827, HCC827ER, and H1975 cell lines as well as xenograft nude mice were selected as models to study the effects of HJD. The proapoptotic effects of HJD were examined by CCK­8 and apoptosis assays. ELISA, immunostaining, and western blot analysis were also performed. HJD considerably enhanced the anticancer effect of erlotinib in both EGFR­TKI­resistant and ­sensitive NSCLC cells. HJD promoted erlotinib­induced apoptosis and caspase 3 activity. The co­treatment also inhibited the expression of Bcl­XL, Bcl­2, and p­STAT3. In addition, siSTAT3 had similar functions with HJD. In particular, the apoptotic rates of erlotinib­stimulated HCC827, HCC827ER, and H1975 cells were enhanced by transfecting siSTAT3. Furthermore, overexpression of STAT3 significantly inhibited HJD­mediated erlotinib sensitization. The combined use of HJD with erlotinib significantly reduced tumor growth in erlotinib­resistant HCC827ER and H1975 xenografts, induced caspase 3, and inhibited Ki67, STAT3, and Bcl­2 expression. HJD significantly alleviated erlotinib resistance by regulating the STAT3/Bcl­2 signaling pathway, which is a promising method to overcome the EGFR­TKI resistance of NSCLC.

Targeting Bcl-2 Family Proteins: What, Where, When?

Proteins of the Bcl-2 family are known as regulators of apoptosis, one of the most studied forms of programmed cell death. The Bcl-2 protein family is represented by both pro- and antiapoptotic members. Antiapoptotic proteins are often exploited by tumor cells to avoid their death, thus playing an important role in carcinogenesis and in acquisition of resistance to various therapeutic agents. Therefore, antiapoptotic proteins represent attractive targets for cancer therapy. A detailed investigation of interactions between Bcl-2 family proteins resulted in the development of highly selective inhibitors of individual antiapoptotic members. These agents are currently being actively studied at the preclinical and clinical stages and represent a promising therapeutic strategy, which is highlighted by approval of venetoclax, a selective inhibitor of Bcl-2, for medical use. Meanwhile, inhibition of antiapoptotic Bcl-2 family proteins has significant therapeutic potential that is yet to be revealed. In the coming era of precision medicine, a detailed study of the mechanisms responsible for the sensitivity or resistance of tumor cells to various therapeutic agents, as well as the search for the most effective combinations, is of great importance. Here, we discuss mechanisms of how the Bcl-2 family proteins function, principles of their inhibition by small molecules, success of this approach in cancer therapy, and, eventually, biochemical features that can be exploited to improve the use of Bcl-2 family inhibitors as anticancer drugs.

The third model of Bax/Bak activation: a Bcl-2 family feud finally resolved?

Bax and Bak, two functionally similar, pro-apoptotic proteins of the Bcl-2 family, are known as the gateway to apoptosis because of their requisite roles as effectors of mitochondrial outer membrane permeabilization (MOMP), a major step during mitochondria-dependent apoptosis. The mechanism of how cells turn Bax/Bak from inert molecules into fully active and lethal effectors had long been the focal point of a major debate centered around two competing, but not mutually exclusive, models: direct activation and indirect activation. After intensive research efforts for over two decades, it is now widely accepted that to initiate apoptosis, some of the BH3-only proteins, a subclass of the Bcl-2 family, directly engage Bax/Bak to trigger their conformational transformation and activation. However, a series of recent discoveries, using previously unavailable CRISPR-engineered cell systems, challenge the basic premise that undergirds the consensus and provide evidence for a novel and surprisingly simple model of Bax/Bak activation: the membrane (lipids)-mediated spontaneous model. This review will discuss the evidence, rationale, significance, and implications of this new model.

LncRNA HORAS5 promotes taxane resistance in castration-resistant prostate cancer via a BCL2A1-dependent mechanism.

Background: Castration-resistant prostate cancer (CRPC) is an incurable malignancy. Long noncoding RNAs (lncRNAs) play key roles in drug resistance. Materials & methods: LncRNA HORAS5 role in cabazitaxel resistance (i.e., cell-count, IC50 and caspase activity) was studied via lentiviral-mediated overexpression and siRNA-based knockdown. Genes expression was analyzed with RNA-sequencing, reverse transcription quantitative PCR (RT-qPCR) and western blot. HORAS5 expression was queried in clinical database. Results: Cabazitaxel increased HORAS5 expression that upregulated BCL2A1, thereby protecting CRPC cells from cabazitaxel-induced apoptosis. BCL2A1 knockdown decreased cell-count and increased apoptosis in CRPC cells. HORAS5-targeting antisense oligonucleotide decreased cabazitaxel IC50. In CRPC clinical samples, HORAS5 expression increased upon taxane treatment. Conclusion:HORAS5 stimulates the expression of BCL2A1 thereby decreasing apoptosis and enhancing cabazitaxel resistance in CRPC cells.

The novel dual BET/HDAC inhibitor TW09 mediates cell death by mitochondrial apoptosis in rhabdomyosarcoma cells.

Targeting the epigenome of cancer cells with the combination of Bromodomain and Extra Terminal (BET) protein inhibitors and histone deacetylase (HDAC) inhibitors has shown synergistic antitumor effects in several cancer types. In this study, we investigate the antitumor potential of the novel dual BET/HDAC inhibitor TW09 in rhabdomyosarcoma (RMS) cells. TW09 reduces cell viability, suppresses long-term clonogenic survival and induces cell death in RMS cells in a dose-dependent manner. Compared to BET/HDAC co-inhibition using JQ1 and MS-275, TW09 induces similar cell death at equimolar concentrations and regulates BET and HDAC target proteins (e.g. c-MYC, H3 acetylation). Mechanistic studies revealed that TW09 upregulates BIM, NOXA, PUMA and BMF, while downregulating BCL-XL, leading to proapoptotic rebalancing of BCL-2 proteins. This results in BAK and BAX activation and caspase-dependent apoptosis, since individual genetic silencing of BIM, NOXA, PUMA, BMF, BAK or BAX, overexpression of BCL-2 or the caspase inhibition with zVAD.fmk all rescue JQ1/BYL719-induced cell death. In conclusion, TW09 shows potent antitumor activity in RMS cells in vitro by inducing mitochondrial apoptosis and may represent a promising new therapeutic option for the treatment of RMS.

Cyclodextrin Prevents Abdominal Aortic Aneurysm via Activation of Vascular Smooth Muscle Cell Transcription Factor EB.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a severe aortic disease with a high mortality rate in the event of rupture. Pharmacological therapy is needed to inhibit AAA expansion and prevent aneurysm rupture. Transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, is critical to maintain cell homeostasis. In this study, we aim to investigate the role of vascular smooth muscle cell (VSMC) TFEB in the development of AAA and establish TFEB as a novel target to treat AAA. METHODS: The expression of TFEB was measured in human and mouse aortic aneurysm samples. We used loss/gain-of-function approaches to understand the role of TFEB in VSMC survival and explored the underlying mechanisms through transcriptome and functional studies. Using VSMC-selective Tfeb knockout mice and different mouse AAA models, we determined the role of VSMC TFEB and a TFEB activator in AAA in vivo. RESULTS: We found that TFEB is downregulated in both human and mouse aortic aneurysm lesions. TFEB potently inhibits apoptosis in VSMCs, and transcriptome analysis revealed that TFEB regulates apoptotic signaling pathways, especially apoptosis inhibitor B-cell lymphoma 2. B-cell lymphoma 2 is significantly upregulated by TFEB and is required for TFEB to inhibit VSMC apoptosis. We consistently observed that TFEB deficiency increases VSMC apoptosis and promotes AAA formation in different mouse AAA models. Furthermore, we demonstrated that 2-hydroxypropyl-ß-cyclodextrin, a clinical agent used to enhance the solubility of drugs, activates TFEB and inhibits AAA formation and progression in mice. Last, we found that 2-hydroxypropyl-ß-cyclodextrin inhibits AAA in a VSMC TFEB-dependent manner in mouse models. CONCLUSIONS: Our study demonstrated that TFEB protects against VSMC apoptosis and AAA. TFEB activation by 2-hydroxypropyl-ß-cyclodextrin may be a promising therapeutic strategy for the prevention and treatment of AAA.

Anti-Apoptotic Molecule BCL2 Is a Therapeutic Target in Steroid-Refractory Graft-Versus-Host Disease.

Graft-versus-host disease (GVHD) is the leading cause of mortality after hematopoietic stem cell transplantation and primarily affects barrier organs such as the skin. One-third of cases are refractory to steroid treatment resulting in poor outcomes and the need for novel therapies. Longitudinal analysis of T-cell transcriptomes in patients before the appearance of GVHD symptoms revealed the upregulation of anti-apoptotic regulator B-cell lymphoma 2 (BCL2) at GVHD initiation. To determine the potential of BCL2 inhibition in active GVHD, we analyzed tissues of 88 patients with acute or chronic GVHD. BCL2 RNA was elevated in multiple organs affected by GVHD and expression correlated with transplant-related mortality and steroid-refractory GVHD. BCL2-expressing lymphocytes were present in skin lesions and peripheral blood of patients with acute and chronic GVHD. Inhibition of BCL2 increased the CD4 to CD8 ratio in allogeneic T cells in vitro and induced apoptosis of T cells from patients with steroid-pretreated chronic GVHD ex vivo. In addition, the higher ratio of regulatory to nonregulatory T cells upon blockage of BCL2 could add to the anti-inflammatory effect of BCL2 blockage. Collectively, our results highlight BCL2 as an important factor for GVHD development and introduce BCL2 inhibition as previously unreported and urgently needed targeted therapy in the treatment of steroid-refractory GVHD.

The ZIKA Virus Delays Cell Death Through the Anti-Apoptotic Bcl-2 Family Proteins.

Zika virus (ZIKV) is an emerging human mosquito-transmitted pathogen of global concern, known to be associated with complications such as congenital defects and neurological disorders in adults. ZIKV infection is associated with induction of cell death. However, previous studies suggest that the virally induced apoptosis occurs at a slower rate compared to the course of viral production. In this present study, we investigated the capacity of ZIKV to delay host cell apoptosis. We provide evidence that ZIKV has the ability to interfere with apoptosis whether it is intrinsically or extrinsically induced. In cells expressing viral replicon-type constructions, we show that this control is achieved through replication. Finally, our work highlights an important role for anti-apoptotic Bcl-2 family protein in the ability of ZIKV to control apoptotic pathways, avoiding premature cell death and thereby promoting virus replication in the host-cell.

Bcl-2 Expression in Pericytes and Astrocytes Impacts Vascular Development and Homeostasis.

B-cell lymphoma 2 (Bcl-2) protein is the founding member of a group of proteins known to modulate apoptosis. Its discovery set the stage for identification of family members with either pro- or anti-apoptotic properties. Expression of Bcl-2 plays an important role during angiogenesis by influencing not only vascular cell survival, but also migration and adhesion. Although apoptosis and migration are postulated to have roles during vascular remodeling and regression, the contribution of Bcl-2 continues to emerge. We previously noted that the impaired retinal vascularization and an inability to undergo pathologic neovascularization observed in mice globally lacking Bcl-2 did not occur when mice lacked the expression of Bcl-2 only in endothelial cells. To further examine the effect of Bcl-2 expression during vascularization of the retina, we assessed its contribution in pericytes or astrocytes by generating mice with a conditional Bcl-2 allele (Bcl-2Flox/Flox) and Pdgfrb-cre (Bcl-2PC mice) or Gfap-cre (Bcl-2AC mice). Bcl-2PC and Bcl-2AC mice demonstrated increased retinal vascular cell apoptosis, reduced numbers of pericytes and endothelial cells and fewer arteries and veins in the retina. Bcl-2PC mice also demonstrated delayed advancement of the superficial retinal vascular layer and aberrant vascularization of the deep vascular plexus and central retina. Although pathologic neovascularization in oxygen-induced ischemic retinopathy (OIR) was not affected by lack of expression of Bcl-2 in either pericytes or astrocytes, laser-induced choroidal neovascularization (CNV) was significantly reduced in Bcl-2PC mice compared to littermate controls. Together these studies begin to reveal how cell autonomous modulation of apoptosis in vascular cells impacts development and homeostasis.

Single-Cell Transcriptomics Identifies the Adaptation of Scart1+ Vγ6+ T Cells to Skin Residency as Activated Effector Cells.

IL-17-producing γδ T cells express oligoclonal Vγ4+ and Vγ6+ TCRs, mainly develop in the prenatal thymus, and later persist as long-lived self-renewing cells in all kinds of tissues. However, their exchange between tissues and the mechanisms of their tissue-specific adaptation remain poorly understood. Here, single-cell RNA-seq profiling identifies IL-17-producing Vγ6+ T cells as a highly homogeneous Scart1+ population in contrast to their Scart2+ IL-17-producing Vγ4+ T cell counterparts. Parabiosis demonstrates that Vγ6+ T cells are fairly tissue resident in the thymus, peripheral lymph nodes, and skin. There, Scart1+ Vγ6+ T cells display tissue-specific gene expression signatures in the skin, characterized by steady-state production of the cytokines IL-17A and amphiregulin as well as by high expression of the anti-apoptotic Bcl2a1 protein family. Together, this study demonstrates how Scart1+ Vγ6+ T cells undergo tissue-specific functional adaptation to persist as effector cells in their skin habitat.

A non-death function of the mitochondrial apoptosis apparatus in immunity.

Apoptosis is a frequent form of programmed cell death, but the apoptotic signaling pathway can also be engaged at a low level, in the absence of cell death. We here report that such sub-lethal engagement of mitochondrial apoptosis signaling causes the secretion of cytokines from human epithelial cells in a process controlled by the Bcl-2 family of proteins. We further show that sub-lethal signaling of the mitochondrial apoptosis pathway is initiated by infections with all tested viral, bacterial, and protozoan pathogens and causes damage to the genomic DNA. Epithelial cells infected with these pathogens secreted cytokines, and this cytokine secretion upon microbial infection was substantially reduced if mitochondrial sub-lethal apoptosis signaling was blocked. In the absence of mitochondrial pro-apoptotic signaling, the ability of epithelial cells to restrict intracellular bacterial growth was impaired. Triggering of the mitochondrial apoptosis apparatus thus not only causes apoptosis but also has an independent role in immune defense.