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.

/pdf/molecular-definitions-of-cell-death-subroutines-q5g428rlyi.pdf

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.

Regulation of gene transcription is the initial step in the complex process that controls gene expression within bacteria. Transcriptional control involves the joint effort of RNA polymerases and numerous other regulatory factors. Whether global or local, positive or negative, regulators play an essential role in the bacterial cell. For instance, some regulators specifically modify the transcription of virulence genes, thereby being indispensable to pathogenic bacteria. Here, we provide a comprehensive overview of important transcription factors and DNA-binding proteins described for the virulent bacterium Francisella tularensis, the causative agent of tularemia. This is an unexplored research area, and the poorly described networks of transcription factors merit additional experimental studies to help elucidate the molecular mechanisms of pathogenesis in this bacterium, and how they contribute to disease.

https://www.mdpi.com/2076-2607/8/10/1622/pdf

Control of Francisella tularensis Virulence at Gene Level: Network of Transcription Factors

Whereas the complete genome of Coxiella burnetii (C.b.), the etiological agent of Q-fever, has recently been published (Seshadri et al., Proc. Natl. Acad. Sci. USA. 100, 5455-5460, 2003), the C.b. proteome is still under study. Using the bioinformatic approach, we found in total 309 proteins on two dimensional electroctrophoretic images of C.b. whole cell lysates. Eighteen major protein species were subjected to peptide mass fingerprinting and identified as the products of 6 known open reading frames (ORFs): the chaperone DnaK (heat shock 70 K protein), chaperonin 60 K (GroEL protein, heat shock protein B), DnaJ-like protein djlA (mucoidy activation protein mucZ), elongation factor Ts (EF-Ts), ribosomal protein L7/L12, and chaperonin 10 K (GroES protein, heat shock protein A).

Initial peptide mass fingerprinting analysis of proteins obtained by lysis of Coxiella burnetii cells.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is well known for its involvement in numerous non-metabolic processes inside mammalian cells. Alternative functions of prokaryotic GAPDH are mainly deduced from its extracellular localization and ability to bind to selected host proteins. Data on its participation in intracellular bacterial processes are scarce, as there has been to date only one study dealing with this issue. We previously have reported several points of evidence that the GAPDH homologue of Francisella tularensis, GapA, might also exert additional non-enzymatic functions. Following on from our earlier observations, we decided to identify GapA’s interacting partners within the bacterial proteome and to explore its new roles at intracellular level. The quantitative proteomics approach based on stable isotope labelling of amino acids in cell culture (SILAC) in combination with affinity purification and mass spectrometry enabled us to identify 18 proteins potentially interacting with GapA. Six of those interactions were further confirmed by alternative methods. Half of the identified proteins were involved in non-metabolic processes. Further analysis together with quantitative label-free comparative analysis of proteomes isolated from the wild-type strain and strain with deleted gapA gene suggests that GapA is implicated in DNA repair processes. Absence of GapA promotes secretion of its most potent interaction partner, the hypothetical protein with peptidase propeptide domain (PepSY), thereby indicating that it impacts on subcellular distribution of some proteins.

/pdf/identification-of-bacterial-protein-interaction-partners-sbxd1q1ejb.pdf

Identification of Bacterial Protein Interaction Partners Points to New Intracellular Functions of Francisella tularensis Glyceraldehyde-3-Phosphate Dehydrogenase.

Francisella tularensis the etiological agent of tularaemia is one of the most infectious human pathogen known. Our knowledge about its key virulence factors has increased recently but it still remains a lot to explore. One of the described essential virulence factors is membrane lipoprotein FTS\_1067 (nomenclature of F. tularensis subsp. holarctica strain FSC200) with homology to the protein family of disulphide oxidoreductases DsbA. Lipoprotein consists of two different domains: the C-terminal DsbA\_Com1-like domain (DSBA-like) and the N-terminal FKBP-type peptidyl-prolyl cis / trans isomerases (FKBP\_N-like). To uncover the biological role of these domains, we created bacterial strain with deletion of the DSBA-like domain. This defect in gene coding for lipoprotein FTS\_1067 led to high in vivo attenuation associated with the ability to induce host protective immunity. Analyses performed with the truncated recombinant protein showed that the absence of DSBA-like domain revealed the loss of thiol/disulphide oxidoreductase activity and, additionally, confirmed the role of the FKBP\_N-like domain in the FTS\_1067 oligomerization and chaperone-like function. Finally, we verified that only full-length form of FTS\_1067 recombinant protein possesses the isomerase activity. Based on our results, we proposed that for the correct FTS\_1067 protein function both domains are needed.

/pdf/cooperation-of-both-the-fkbp-n-like-and-the-dsba-like-52oob16gql.pdf

Cooperation of both, the FKBP_N-like and the DSBA-like, domains is necessary for the correct function of FTS_1067 protein involved in Francisella tularensis virulence and pathogenesis

Jiri Stulik

Papers

Control of Francisella tularensis Virulence at Gene Level: Network of Transcription Factors

Initial peptide mass fingerprinting analysis of proteins obtained by lysis of Coxiella burnetii cells.

Identification of Bacterial Protein Interaction Partners Points to New Intracellular Functions of Francisella tularensis Glyceraldehyde-3-Phosphate Dehydrogenase.

Cooperation of both, the FKBP_N-like and the DSBA-like, domains is necessary for the correct function of FTS_1067 protein involved in Francisella tularensis virulence and pathogenesis

Tetratricopeptide Repeat Motifs in the World of Bacterial Pathogens; Role in Virulence 1