Table of contents

Volume 2, Issue 7, pp. 216 - 258, July 2015

Issue cover

The cover image, captured by multiphoton microscopy (with the support of the Imagopole, Institut Pasteur), shows the invasion of human colonic mucosa rich in collagen (green) by Entamoeba histolytica (red). Image by Roman Thibeaux (Institut Pasteur, Paris, France); modified by MIC. The cover is published under the Creative Commons Attribution (CC BY) license. Enlarge issue cover


Entamoeba histolytica – tumor necrosis factor: a fatal attraction

Serge Ankri

page 216-218 | 10.15698/mic2015.07.216 | Full text | PDF |


Wanted Plasmodium falciparum, dead or alive

Fatimata Sow, Mary Nyonda, Anne-Lise Bienvenu, Stephane Picot

page 219-224 | 10.15698/mic2015.07.211 | Full text | PDF | Abstract

Mechanisms of cell death in unicellular parasites have been subjects of debate for the last decade, with studies demonstrating evidence of apoptosis or non-apoptosis like mechanisms, including necrosis, and autophagy. Recent clarifications on the definition of regulated or accidental cell death by The Nomenclature Committee on Cell Death provides an opportunity to reanalyze some data, re-evaluate conclusions in the light of parasite diversity, and to propose alternative arguments in the context of malaria drug resistance, considering lack of really new drugs in the pipeline. Deciphering the mechanisms of death may help in detection of new drug targets and the design of innovative drugs. However, classifications have been evolving rapidly since initial description of “programmed cell death”, leading to some uncertainty as to whether Plasmodium cell death is accidental or regulated.

Yeast as a tool to explore cathepsin D function

H. Pereira, C.S.F. Oliveira, L. Castro, A. Preto, S. R. Chaves, M. Côrte-Real

page 225-234 | 10.15698/mic2015.07.212 | Full text | PDF | Abstract

Cathepsin D has garnered increased attention in recent years, mainly since it has been associated with several human pathologies. In particular, cathepsin D is often overexpressed and hypersecreted in cancer cells, implying it may constitute a therapeutic target. However, cathepsin D can have both anti- and pro-survival functions depending on its proteolytic activity, cellular context and stress stimulus. Therefore, a more detailed understanding of cathepsin D regulation and how to modulate its apoptotic functions is clearly needed. In this review, we provide an overview of the role of cathepsin D in physiological and pathological scenarios. We then focus on the opposing functions of cathepsin D in apoptosis, particularly relevant in cancer research. Emphasis is given to the role of the yeast protease Pep4p, the vacuolar counterpart of cathepsin D, in life and death. Finally, we discuss how insights from yeast cathepsin D and its role in regulated cell death can unveil novel functions of mammalian cathepsin D in apoptosis and cancer.

Research Articles

In Entamoeba histolytica, a BspA family protein is required for chemotaxis toward tumour necrosis factor

Anne Silvestre, Aurélie Plaze, Patricia Berthon, Roman Thibeaux, Nancy Guillen and Elisabeth Labruyère

page 235-246 | 10.15698/mic2015.07.214 | Full text | PDF | Abstract

Background: Entamoeba histolytica cell migration is essential for the development of human amoebiasis (an infectious disease characterized by tissue invasion and destruction). The tissue inflammation associated with tumour necrosis factor (TNF) secretion by host cells is a well-documented feature of amoebiasis. Tumour necrosis factor is a chemoattractant for E. histolytica, and the parasite may have a TNF receptor at its cell surface. Methods: confocal microscopy, RNA Sequencing, bioinformatics, RNA antisense techniques and histological analysis of human colon explants were used to characterize the interplay between TNF and E. histolytica. Results: an antibody against human TNF receptor 1 (TNFR1) stained the E. histolytica trophozoite surface and (on immunoblots) binds to a 150-kDa protein. Proteome screening with the TNFR1 sequence revealed a BspA family protein in E. histolytica that carries a TNFR signature domain and six leucine-rich repeats (named here as “cell surface protein”, CSP, in view of its cellular location). Cell surface protein shares structural homologies with Toll-Like receptors, colocalizes with TNF and is internalized in TNF-containing vesicles. Reduction of cellular CSP levels abolished chemotaxis toward TNF and blocked parasite invasion of human colon. Conclusions: there is a clear link between TNF chemotaxis, CSP and pathogenesis.

Research Reports

Human Thyroid Cancer-1 (TC-1) is a vertebrate specific oncogenic protein that protects against copper and pro-apoptotic genes in yeast

Natalie K. Jones, Nagla T.T. Arab, Rawan Eid, Nada Gharib, Sara Sheibani, Hojatollah Vali, Chamel Khoury, Alistair Murray, Eric Boucher, Craig A. Mandato, Paul G. Young and Michael T. Greenwood

page 247-255 | 10.15698/mic2015.07.213 | Full text | PDF | Abstract

The human Thyroid Cancer-1 (hTC-1) protein, also known as C8orf4 was initially identified as a gene that was up-regulated in human thyroid cancer. Here we show that hTC-1 is a peptide that prevents the effects of over-expressing Bax in yeast. Analysis of the 106 residues of hTC-1 in available protein databases revealed direct orthologues in jawed-vertebrates, including mammals, frogs, fish and sharks. No TC-1 orthologue was detected in lower organisms, including yeast. Here we show that TC-1 is a general pro-survival peptide since it prevents the growth- and cell death-inducing effects of copper in yeast. Human TC-1 also prevented the deleterious effects that occur due to the over-expression of a number of key pro-apoptotic peptides, including YCA1, YBH3, NUC1, and AIF1. Even though the protective effects were more pronounced with the over-expression of YBH3 and YCA1, hTC-1 could still protect yeast mutants lacking YBH3 and YCA1 from the effects of copper sulfate. This suggests that the protective effects of TC-1 are not limited to specific pathways or processes. Taken together, our results indicate that hTC-1 is a pro-survival protein that retains its function when heterologously expressed in yeast. Thus yeast is a useful model to characterize the potential roles in cell death and survival of cancer related genes.


Evolutionary rewiring of bacterial regulatory networks

Tiffany B. Taylor, Geraldine Mulley, Liam J. McGuffin, Louise J. Johnson, Michael A. Brockhurst, Tanya Arseneault, Mark W. Silby and Robert W. Jackson

page 256-258 | 10.15698/mic2015.07.215 | Full text | PDF | Abstract

Bacteria have evolved complex regulatory networks that enable integration of multiple intracellular and extracellular signals to coordinate responses to environmental changes. However, our knowledge of how regulatory systems function and evolve is still relatively limited. There is often extensive homology between components of different networks, due to past cycles of gene duplication, divergence, and horizontal gene transfer, raising the possibility of cross-talk or redundancy. Consequently, evolutionary resilience is built into gene networks – homology between regulators can potentially allow rapid rescue of lost regulatory function across distant regions of the genome. In our recent study [Taylor, et al. Science (2015), 347(6225)] we find that mutations that facilitate cross-talk between pathways can contribute to gene network evolution, but that such mutations come with severe pleiotropic costs. Arising from this work are a number of questions surrounding how this phenomenon occurs.