A touch of Zen: post-translational regulation of theLeishmaniastress response

Abstract

SummaryAcross bacterial, archaeal and eukaryotic kingdoms, heat shock proteins (HSPs) are defined as a class of highly conserved chaperone proteins that are rapidly induced in response to temperature increase through dedicated heat shock transcription factors. While this transcriptional response governs cellular adaptation of fungal, plant and animal cells to thermic shock and other forms of stress, early-branching eukaryotes of the kinetoplastid order, including trypanosomatid parasites, lack classical mechanisms of transcriptional regulation and show largely constitutive expression of HSPs, thus raising important questions on the function of HSPs in the absence of stress and the regulation of their chaperone activity in response to environmental adversity. Understanding parasite-specific mechanisms of stress-response regulation is especially relevant for protozoan parasites of the genus Leishmania that are adapted for survival inside highly toxic phagolysosomes of host macrophages causing the various immuno-pathologies of leishmaniasis. Here we review recent advances on the function and regulation of chaperone activities in these kinetoplastid pathogens and propose a new model for stress-response regulation through a reciprocal regulatory relationship between stress kinases and chaperones that may be relevant for parasiteadaptive differentiation and infectivity.

Modulation of Aneuploidy in Leishmania donovani during Adaptation to Different In Vitro and In Vivo Environments and Its Impact on Gene Expression

“…While chromosome copy number is mirrored by transcript levels in this study, these should be also reflected at the protein and metabolite levels to have a phenotypic effect. Although genes are constantly transcribed in a polycistronic manner by this process, it is likely that only a few specific genes required for adaptation to a given environment are the main drivers, with the expression levels of other genes regulated via posttranscriptional mechanisms (32). In our data set, we observed that although an overall correlation between the quantities of DNA and RNA exists, not all individual transcripts found on variable chromosomes change to the same extent: this was most obvious in the case of snoRNAs in chromosome 5 and one amastin array in chromosome 8.…”

A study of bias and increasing organismal complexity from their post-translational modifications and reaction site interplays

“…For instance, protein stress may result from an event or treatment, which leads to protein failure when the protein is forced to sustain its duties under unnatural circumstances, such as environmental stress. Across seemingly all proteins, PTMs offer an extremely rapid solution for withstanding naturally occurring environmental stresses, such as microgravity [10], drought [11], thermic shock [12,13] and others. Stress responses resulting from the proteins themselves are also conducted by phosphorylation as in the case of initiation and regulation of tumor suppression by the p53 complex [6] and SUMOylation for its response to oxidative stress [7].…”

Leishmania hijacking of the macrophage intracellular compartments

“…Macrophage‐internalized amastigotes are able to replicate and persist intracellularly, triggering long‐term latent infections that can lead to reactivation of disease years or decades after the primary infection. Both promastigotes and amastigotes of Leishmania are able to regulate the maturation of the parasitophorous vacuole in order to make it more hospitable and avoid destruction by the macrophage microbicidal activity and to overcome the host immune defense responses . For that purpose, macrophage defenses such as oxidative damage, antigen presentation, immune activation and apoptosis are compromised, and the parasite reprograms the macrophage to promote infection .…”

“…The phagosome achieves maturation by fusion with late endosomes and lysosomes resulting in the acquisition of lysosome‐associated molecules including LAMP‐1 and ‐2 , and cathepsins B, D, H and L . This phenomenon leads to a drop in pH and an elevation of temperature in the parasitophorous vacuole . It has been proposed that the acidic pH and high temperature participate in the developmental transition of the promastigote to the amastigote form, with the involvement of other signals including stress signals being probable .…”

“…This phenomenon leads to a drop in pH and an elevation of temperature in the parasitophorous vacuole . It has been proposed that the acidic pH and high temperature participate in the developmental transition of the promastigote to the amastigote form, with the involvement of other signals including stress signals being probable . The differentiation of the promastigote form into the amastigote form results in a loss or reduction of the flagellum since the amastigote shows an internal residual flagellum, and a change in the cell surface LPG .…”