High-Mobility-Group Box Nuclear Factors of Plasmodium falciparum

Abstract

In eukaryotes, the high-mobility-group (HMG) nuclear factors are highly conserved throughout evolution and are divided into three families, including HGMB, characterized by an HMG box domain. Some HMGB factors are DNA structure specific and preferentially interact with distorted DNA sequences, trigger DNA bending, and hence facilitate the binding of nucleoprotein complexes that in turn activate or repress transcription. In Plasmodium falciparum, two HMGB factors were predicted: PfHMGB1 and PfHMGB2. They are small proteins, under 100 amino acids long, encompassing a characteristic HMG box domain closely related to box B of metazoan factors, which comprises two HMG box domains, A and B, in tandem. Computational analyses supported the conclusion that the Plasmodium proteins were genuine architectural HMGB factors, and in vitro analyses performed with both recombinant proteins established that they were able to interact with distorted DNA structures and bend linear DNA with different affinities. These proteins were detected in both asexual-and gametocyte-stage cells in Western blotting experiments and mainly in the parasite nuclei. PfHMGB1 is preferentially expressed in asexual erythrocytic stages and PfHMGB2 in gametocytes, in good correlation with transcript levels of expression. Finally, immunofluorescence studies revealed differential subcellular localizations: both factors were observed in the nucleus of asexual-and sexual-stage cells, and PfHMGB2 was also detected in the cytoplasm of gametocytes. In conclusion, in light of differences in their levels of expression, subcellular localizations, and capacities for binding and bending DNA, these factors are likely to play nonredundant roles in transcriptional regulation of Plasmodium development in erythrocytes.Malaria is the most important parasitic disease in the world, and of the 300 to 500 million cases each year, approximately 2 million people die. Among the four species of malaria parasites infecting humans, Plasmodium falciparum causes the highest morbidity and mortality. Global efforts to eradicate malaria have failed, and there is presently no effective vaccine available. Therefore, a greater understanding of parasite biology throughout development is urgently needed in order for novel therapeutic strategies to control malaria to be proposed.During the erythrocytic life cycle, intense multiplication of parasites takes place, as well as gametocyte differentiation associated with cell cycle arrest. These different developmental pathways require the coordinated and modulated expression of diverse sets of genes, involving transcriptional, epigenetic, and posttranscriptional regulation. Currently, it is commonly accepted that general mechanisms involved in gene regulation in eukaryotes also operate in P. falciparum (25,32,33). Nevertheless, elucidation of the molecular mechanisms involved in transcriptional regulation in Plasmodium is still challenging.Even if very little is known about the cis-and trans-regulatory elements of the parasite, Plasmodium genes exh...

The origins of apicomplexan sequence innovation

“…While their classification as apicomplexan-specialized proteins may be surprising, inspection of their alignments expose variation between apicomplexan ribosomal proteins and those for other species (Supplemental File S1). Similar findings were observed for a group of chromatinrelated factors annotated as ''high mobility group'' proteins (Briquet et al 2006). Numerous gene duplication events have occurred in the Plasmodium and Toxoplasmatinae lineages, revealing potential differences in transcription regulation associated with each parasitic life cycle (Fig.…”

High Mobility Group Protein HMGB2 Is a Critical Regulator of Plasmodium Oocyst Development

“…Interestingly, these HMGB are differentially expressed. HMGB1 is expressed during the erythrocytic asexual cycle, whereas HMGB2 is slightly expressed at the schizont stage and highly expressed at the gametocyte stage (2,16).…”

“…HMGB proteins also actively participate in chromatin remodeling by increasing nucleosome sliding and accessibility of the chromatin (17). The two Plasmodium falciparum HMGB proteins, HMGB1 (PFL0145c) and HMGB2 (MAL8P1.72), have the biochemical characteristics of the HMGB box family of transcriptional regulators (16). Interestingly, these HMGB are differentially expressed.…”

“…Two proteins containing a high mobility group box (HMGB) 3 are highly conserved among Plasmodium species (16). HMGB box proteins are small transcriptional regulators that bind DNA in a nonsequence-specific fashion and bend it, leading to the recruitment of RNA polymerase II and the induction of transcription (17).…”

Strong renal expression of heat shock protein 70, high mobility group box 1, inducible nitric oxide synthase, and nitrotyrosine in mice model of severe malaria

“…For example, Wu et al reported that HMGB1 expression was increased in AKI, and reportedly causes kidney damage through activation of the innate immune system 26 . In this context, HMGB1 triggers cellular signaling by binding to TLR4, which activates NFkB through a MyD88-dependent pathway and initiates the inflammatory response by releasing pro-inflammatory cytokines and chemokines 27 . Moreover, HMGB1 directly induces prothrombin expression on endothelial cells, which can contribute to the inflammatory response and exacerbate any renal impairment 12 .…”