A regulatory role for the 5′ and 3′ untranslated regions in differential expression of hsp83 in<i>Leishmania</i>

Aly, Radi; Argaman, Miriam; Halman, Segula; Shapira, Michael Y.

doi:10.1093/nar/22.15.2922

Cited by 80 publications

(54 citation statements)

References 48 publications

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“…probably proceeds unidirectionally (Myler et al, 1999) and is mostly constitutive: gene expression is regulated at the levels of RNA processing, RNA stability, and/or translation control (Curotto de Lafaille et al, 1992;Aly et al, 1994;Brandau et al, 1995;Graham, 1995;Teixeira, 1998;Stiles et al, 1999). Nevertheless, Hsp90 can obviously chaperone the factors involved at these levels of regulation as well.…”

Section: A Role For Hsp90 In Posttranscriptional Stress Responsementioning

confidence: 99%

Heat Shock Protein 90 Homeostasis Controls Stage Differentiation in Leishmania donovani

Wiesgigl

Clos

2001

MBoC

186

177

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The differentiation of Leishmania parasites from the insect stage, the promastigote, toward the pathogenic mammalian stage, the amastigote, is triggered primarily by the rise in ambient temperature encountered during the insect-to-mammal transmission. We show here that inactivation of heat shock protein (Hsp) 90, with the use of the drugs geldanamycin or radicicol, mimics transmission and induces the differentiation from the promastigote to the amastigote stage. Geldanamycin also induces a growth arrest of cultured promastigotes that can be forestalled by overexpression of the cytoplasmic Hsp90. Moreover, we demonstrate that Hsp90 serves as a feedback inhibitor of the cellular heat shock response in Leishmania. Our results are consistent with Hsp90 homeostasis serving as cellular thermometer for these primitive eukaryotes, controlling both the heat shock response and morphological differentiation. INTRODUCTIONProtozoan parasites of the genus Leishmania are transmitted by blood-feeding sand flies to mammalian hosts, including humans, whereby they encounter a rise in ambient temperature. Subjecting cultured insect stages, the promastigotes, of various Leishmania species to a similar temperature upshift in vitro results in the transient posttranscriptional upregulation of both heat shock protein (Hsp) 90 (also known as Hsp83) and Hsp70 synthesis and a persistent induction of Hsp100 expression Brandau et al., 1995;Krobitsch et al., 1998). Moreover, species such as L. mexicana, L. pifanoi, and L. donovani will, during heat stress and acidification of the medium, show a morphological transition toward the mammalian stage, the amastigote (Zilberstein and Shapira, 1994;Saar et al., 1998). Such axenic amastigotes are indistinguishable from true host tissue-derived intracellular amastigotes (Bates, 1993;Pan et al., 1993;Charest and Matlashewski, 1994;Charest et al., 1996;Gupta et al., 1996;Saar et al., 1998). Thus, the rise of temperature encountered during transmission can be viewed not as stress but rather as signal for cellular differentiation.We have shown previously that Hsp100 is critical for the expression of some amastigote stage-specific proteins and for overall virulence of the parasites (Hubel et al., 1997;Krobitsch et al., 1998); however, gene replacement mutants lacking Hsp100 still show, induced by elevated temperature, morphological differentiation to viable amastigote-like culture stages, indicating that the induction of morphological differentiation occurs independently or upstream of Hsp100 (Krobitsch et al., 1998;Krobitsch and Clos, 1999).Another chaperone, Hsp90 (Hsp83), is one of the most abundant proteins in Leishmania, constituting 2.8% of the cellular protein . Hsp90 (Hsp83) is encoded by multiple gene copies and is found in the soluble fraction of the cytoplasm (Shapira and Pinelli, 1989;Brandau et al., 1995;Hubel and Clos, 1996). Its sequence is distinct from the Grp94 homologue of L. infantum, which was characterized recently (Larreta et al., 2000). In higher eukaryotes and in yeast, cytosolic H...

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Section: A Role For Hsp90 In Posttranscriptional Stress Responsementioning

confidence: 99%

Heat Shock Protein 90 Homeostasis Controls Stage Differentiation in Leishmania donovani

Wiesgigl

Clos

2001

MBoC

186

177

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“…Mature mRNAs are subsequently obtained from coordinated polyadenylation and trans-splicing, which adds a 39-nt spliced leader (SL) sequence to the 5' end of all mRNAs [30,31]. As a consequence of this unusual gene organization, Leishmania gene expression appears to not be regulated at the level of transcription [32], but stage-specific expression of a number of genes has been shown to be regulated via mRNA stability [8,[33][34][35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

Analysis of the Leishmania donovani transcriptome reveals an ordered progression of transient and permanent changes in gene expression during differentiation

Saxena

Lahav

Holland

et al. 2007

Molecular and Biochemical Parasitology

148

140

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Leishmania donovani is an intracellular protozoan parasite that causes kala-azar in humans. During infection the extracellular insect forms (promastigotes) undergo rapid differentiation to intracellular amastigotes that proliferates in phagolysosomes of mammalian macrophages. We used microarraybased expression profiling to investigate the time-course of changes in RNA abundance during promastigote-to-amastigote differentiation in a host-free system that mimics this process. These studies revealed that several hundred genes underwent an ordered progression of transient or permanent up-and down-regulation during differentiation. Genes that were permanently upregulated in amastigotes were enriched for transporters and surface proteins, but under-represented in genes involved in protein and other metabolism. Most of these changes occurred late in the differentiation process, when morphological differentiation was essentially complete. Downregulated genes were over-represented in those involved in cell motility, growth and/or maintenance, and these changes generally occurred earlier in the process. Genes that were transiently up-or downregulated during differentiation included those encoding heat shock proteins, ubiquitin hydrolases, RNA binding proteins, protein kinases, a protein phosphatase, and a histone deacetylase. These results suggest that changes in mRNA abundance may be important in signal transduction, as well as protein and mRNA turnover, during differentiation. In addition to these mRNA changes, other transcripts including one or more rRNAs and snoRNAs, and non-coding RNAs from several telomeres, also showed substantial changes in abundance during the differentiation process. This paper provides the first genome-scale quantitative analysis of gene expression during the transition from promastigotes to amastigotes and demonstrates the utility of the host-free differentiation system.

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“…Instead, these genes are constitutively transcribed from large gene clusters, and the steady state levels of their mature mRNAs are regulated post-transcriptionally by mechanisms that often involve their 3Ј-UTR sequences (22)(23)(24)(25)(26)(27)(28). Because the abundance of the PSA and MSPS RNAs in L. chagasi promastigotes are regulated in parallel, we inspected their 3Ј-UTRs to see if their 1.0-kb (MSP) and 1.3-kb (PSA) 3Ј-UTRs contain sequences in common.…”

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confidence: 99%

Comparison of the Post-transcriptional Regulation of the mRNAs for the Surface Proteins PSA (GP46) and MSP (GP63) ofLeishmania chagasi

Myung¹,

Beetham²,

Wilson³

et al. 2002

Journal of Biological Chemistry

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MSP (GP63) and PSA (GP46) are abundant 63-and 46-kDa glycolipid-anchored proteins on the surface of the promastigote form of most Leishmania species. MSP is a zinc metalloprotease that confers resistance to host complement-mediated lysis. PSA contains internal repeats of 24 amino acids, and its function is unknown. The steady state levels of mRNAs for both glycoproteins are regulated post-transcriptionally, resulting in about a 30-fold increase as Leishmania chagasi promastigotes grow in vitro from logarithmic phase to stationary phase. Previous studies showed the 3-untranslated regions (3-UTRs) of these mRNAs are essential for this post-transcriptional regulation. These two 3-UTRs of 1.0 and 1.3 kilobases were cloned immediately downstream of a ␤-galactosidase reporter gene in a plasmid, and segments were systematically deleted to examine which portions of the 3-UTRs contribute to the posttranscriptional regulation. The 92-nucleotide segment of greatest similarity between the two 3-UTRs was deleted without loss of regulation, but the segments flanking this similarity region have positive regulatory elements essential for the regulation. We propose that similar, but non-identical, molecular mechanisms regulate the parallel expression of these two L. chagasi mRNAs despite their lack of sequence identity. These post-transcriptional mechanisms resemble the mechanism recently suggested for the regulation of mRNAs encoding the dipeptide (EP) and pentapeptide (GPEET) repeat proteins in Trypanosoma brucei that involves interactions between positive and negative regulatory elements in the 3-UTR.Protozoan parasites of the genus Leishmania cause a diverse group of diseases collectively called leishmaniasis that range in severity from spontaneously healing cutaneous ulcers to potentially fatal visceral disease. During their life cycle the Leishmania sp. exist as two developmental stages, i.e. as extracellular promastigotes in the gut of the sandfly vector and as intracellular amastigotes in the phagolysosome of mammalian macrophages. Glycoproteins on the surface of the organism play important roles in its survival in both of these environments. The two best characterized Leishmania surface glycoproteins are the major surface protease (MSP, 1 also called GP63 for 63-kDa glycoprotein) and the parasite surface antigen (PSA, also named GP46 for 46-kDa glycoprotein). Although these proteins have historically been called GP63 and GP46, the Nomenclature Working Group for Protozoan Parasites has recommended that protozoan proteins be assigned 3-6-letter names (1), so we will use the nomenclature of MSP and PSA here. Immunization with recombinant versions of either of these proteins or their genes via DNA vaccines provides experimental animals with partial protection against Leishmania challenge (2-6).Leishmania MSP is a family of closely related zinc metalloproteases that have been found in different reports to (i) confer resistance of promastigotes to complement-mediated lysis (7), (ii) promote attachment to and internalization o...

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A regulatory role for the 5′ and 3′ untranslated regions in differential expression of hsp83 inLeishmania

Cited by 80 publications

References 48 publications

Heat Shock Protein 90 Homeostasis Controls Stage Differentiation in Leishmania donovani

Heat Shock Protein 90 Homeostasis Controls Stage Differentiation in Leishmania donovani

Analysis of the Leishmania donovani transcriptome reveals an ordered progression of transient and permanent changes in gene expression during differentiation

Comparison of the Post-transcriptional Regulation of the mRNAs for the Surface Proteins PSA (GP46) and MSP (GP63) ofLeishmania chagasi

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