Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

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Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.

/pdf/targeting-autophagy-in-cancer-2pjcn0h04a.pdf

Targeting autophagy in cancer

How does the host sense pathogens? Our present concepts grew directly from longstanding efforts to understand infectious disease: how microbes harm the host, what molecules are sensed and, ultimately, the nature of the receptors that the host uses. The discovery of the host sensors — the Toll-like receptors — was rooted in chemical, biological and genetic analyses that centred on a bacterial poison, termed endotoxin.

Innate immune sensing and its roots: the story of endotoxin

Macroautophagy/autophagy is a conserved transport pathway where targeted structures are sequestered by phagophores, which mature into autophagosomes, and then delivered into lysosomes for degradati...

/pdf/chloroquine-inhibits-autophagic-flux-by-decreasing-29tresuftu.pdf

Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion.

Ubiquitination of proteins, like phosphorylation and acetylation, is an important regulatory aspect influencing numerous and various cell processes, such as immune response signaling and autophagy. The study of ubiquitination has become essential to learning about host–pathogen interactions, and a better understanding of the detailed mechanisms through which pathogens affect ubiquitination processes in host cell will contribute to vaccine development and effective treatment of diseases. Pathogenic bacteria (e.g., Salmonella enterica, Legionella pneumophila and Shigella flexneri) encode many effector proteins, such as deubiquitinating enzymes (DUBs), targeting the host ubiquitin machinery and thus disrupting pertinent ubiquitin-dependent anti-bacterial response. We focus here upon the host ubiquitination system as an integral unit, its interconnection with the regulation of inflammation and autophagy, and primarily while examining pathogens manipulating the host ubiquitination system. Many bacterial effector proteins have already been described as being translocated into the host cell, where they directly regulate host defense processes. Due to their importance in pathogenic bacteria progression within the host, they are regarded as virulence factors essential for bacterial evasion. However, in some cases (e.g., Francisella tularensis) the host ubiquitination system is influenced by bacterial infection, although the responsible bacterial effectors are still unknown.

https://www.mdpi.com/2076-2607/9/3/638/pdf

The Ubiquitination System within Bacterial Host-Pathogen Interactions.

The presented multistep program for testing immunomodulatory properties of biological response modifiers offers the possibility to evaluate multilaterally the modulatory potential of the tested preparations and to obtain basic data concerning their acute immunotoxicity. The scheme is divided into four stages: screening, optimalization, modelling, and analytical stage, each of which can be carried out separately on a relatively individual basis. This division considers the effect of the preparation on basic functions of the cells participating in the network of immunoregulation, the influence on the course of the immune response, modulation of the reactivity of the immune system affected by a 'non-immunological' phenomenon, as well as changes in protein repertoire produced by different systems of cells exposed to the tested preparation and/or the immunogenic signal. Detailed toxicological evaluation should be performed separately from immunopharmacological evaluation, keeping in mind differences in the application of the substances and the animal model involved. Incorporation of mathematical modelling and computer analysis of the results obtained by using the scheme may prove valuable in solving problems associated with potential modulation of the host immune system in clinically significant situations.

Multistep scheme for testing immunomodulatory substances.

Summary Disulfide bond formation is necessary for a correct folding and a proper function of many secreted proteins. We know that many of these proteins are involved in bacterial virulence and pathogenesis. The best known pathways of disulfide bond formation and isomerization belong to Escherichia coli (E. coli) . This Gram-negative bacterium is usually used as a model organism. This review is aimed initially at

/pdf/the-disulfide-bond-formation-and-its-relationship-to-3twt4u84bp.pdf

The disulfide bond formation and its relationship to bacterial pathogenicity of three important gram-negative bacteria

Francisella tularensis is a highly virulent intracellular pathogen with the capacity to infect a variety of hosts including humans. One of the most important proteins involved in F. tularensis virulence and pathogenesis is the protein DsbA. This protein is annotated as a lipoprotein with disulfide oxidoreductase/isomerase activity. Therefore, its interactions with different substrates, including probable virulence factors, to assist in their proper folding are anticipated. We aimed to use the immunopurification approach to find DsbA (gene locus FTS_1067) interacting partners in F. tularensis subsp. holarctica strain FSC200 and compare the identified substrates with proteins which were found in our previous comparative proteome analysis. As a result of our work two FTS_1067 substrates, D-alanyl-D-alanine carboxypeptidase family protein and HlyD family secretion protein, were identified. Bacterial two-hybrid systems were further used to test their relevance in confirming FTS_1067 protein interactions.

/pdf/identification-of-two-substrates-of-fts-1067-protein-an-3si9jkmkny.pdf

Identification of two substrates of FTS_1067 protein - An essential virulence factor of Francisella tularensis.

Francisella tularensis is a highly infectious bacterium that causes the potentially lethal disease tularemia. This extremely virulent bacterium is able to replicate in the cytosolic compartments of infected macrophages. To invade macrophages and to cope with their intracellular environment, Francisella requires multiple virulence factors, which are still being identified. Proteins containing tetratricopeptide repeat (TPR)-like domains seem to be promising targets to investigate, since these proteins have been reported to be directly involved in virulence-associated functions of bacterial pathogens. Here, we studied the role of the FTS_0201, FTS_0778, and FTS_1680 genes, which encode putative TPR-like proteins in Francisella tularensis subsp. holarctica FSC200. Mutants defective in protein expression were prepared by TargeTron insertion mutagenesis. We found that the locus FTS_1680 and its ortholog FTT_0166c in the highly virulent Francisella tularensis type A strain SchuS4 are required for proper intracellular replication, full virulence in mice, and heat stress tolerance. Additionally, the FTS_1680-encoded protein was identified as a membrane-associated protein required for full cytopathogenicity in macrophages. Our study thus identifies FTS_1680/FTT_0166c as a new virulence factor in Francisella tularensis.

Jiri Stulik

Papers

The Ubiquitination System within Bacterial Host-Pathogen Interactions.

Multistep scheme for testing immunomodulatory substances.

The disulfide bond formation and its relationship to bacterial pathogenicity of three important gram-negative bacteria

Identification of two substrates of FTS_1067 protein - An essential virulence factor of Francisella tularensis.

Characterization of Tetratricopeptide Repeat-Like Proteins in Francisella tularensis and Identification of a Novel Locus Required for Virulence