Abstract
Trypanosoma brucei is the causative agent of African sleeping sickness. The parasite cycles between its insect (procyclic form) and mammalian hosts (bloodstream form). Trypanosomes lack conventional transcription regulation, and their genes are transcribed in polycistronic units that are processed by trans-splicing and polyadenylation. In trans-splicing, which is essential for processing of each mRNA, an exon, the spliced leader (SL) is added to all mRNAs from a small RNA, the SL RNA. Trypanosomes lack the machinery for the unfolded protein response (UPR), which in other eukaryotes is induced under endoplasmic reticulum (ER) stress. Trypanosomes respond to such stress by changing the stability of mRNAs, which are essential for coping with the stress. However, under severe ER stress that is induced by blocking translocation of proteins to the ER, treatment of cells with chemicals that induce misfolding in the ER, or extreme pH, trypanosomes elicit the spliced leader silencing (SLS) pathway. In SLS, the transcription of the SL RNA gene is extinguished, and tSNAP42, a specific SL RNA transcription factor, fails to bind to its cognate promoter. SLS leads to complete shut-off of trans-splicing. In this review, I discuss the UPR in mammals and compare it to the ER stress response in T. brucei leading to SLS. I summarize the evidence supporting the notion that SLS is a programmed cell death (PCD) pathway that is utilized by the parasites to substitute for the apoptosis observed in higher eukaryotes under prolonged ER stress. I present the hypothesis that SLS evolved to expedite the death process, and rapidly remove from the population unfit parasites that, by elimination via SLS, cause minimal damage to the parasite population.
Highlights
Trypanosoma brucei is the causative agent of African sleeping sickness
The trypanosome unfolded protein response (UPR)-response is regulated in a manner similar to the heat-shock response in these organisms by stabilizing the mRNAs which are essential to cope with the endoplasmic reticulum (ER) stress [46]
When the ER stress is prolonged by continued exposure to reducing agents, exposure to extreme pH, or blocking entry to the ER by depletion of ER translocation factors (SRP receptor, SEC63 or SEC61), spliced leader silencing (SLS) is induced
Summary
Trypanosomes possess a UPR-like response despite the lack of the transcriptional-based machinery that conducts this process in other eukaryotes. The two missing links in understanding the mechanism of SLS are: (1) identification of the signaling pathway that senses the ER stress and transmits the signal to the nucleus, and (2) understanding the molecular events underlying the shut-off of SL RNA transcription. We identified an essential kinase (PK-3) whose presence is required for executing SLS. This handle on SLS signaling should lead to discovery of the entire signal transduction pathway. The mechanism underlying SL RNA transcription shut-off remains under investigation, but so far, our data suggest that the mechanism does not involve post-translational modification on tSNAP42. Inducing SLS during infection could offer a powerful means to control trypanosomal diseases such as sleeping sickness. Competing interests The author declares that she has no competing interests
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