Spliced leader RNA silencing (SLS) - a programmed cell death pathway in Trypanosoma brucei that is induced upon ER stress (Parasites & Vectors)

Trypanosoma brucei is the causative agent of African sleeping sickness. The parasite cyclesbetween its insect (procyclic form) and mammalian hosts (bloodstream form). Trypanosomeslack conventional transcription regulation, and their genes are transcribed in polycistronicunits that are processed by trans-splicing and polyadenylation. In trans-splicing, which isessential for processing of each mRNA, an exon, the spliced leader (SL) is added to allmRNAs from a small RNA, the SL RNA. Trypanosomes lack the machinery for the unfoldedprotein response (UPR), which in other eukaryotes is induced under endoplasmic reticulum(ER) stress. Trypanosomes respond to such stress by changing the stability of mRNAs, whichare essential for coping with the stress. However, under severe ER stress that is induced byblocking translocation of proteins to the ER, treatment of cells with chemicals that inducemisfolding 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, aspecific SL RNA transcription factor, fails to bind to its cognate promoter. SLS leads tocomplete shut-off of trans-splicing. In this review, I discuss the UPR in mammals andcompare it to the ER stress response in T. brucei leading to SLS. I summarize the evidencesupporting the notion that SLS is a programmed cell death (PCD) pathway that is utilized bythe parasites to substitute for the apoptosis observed in higher eukaryotes under prolongedER stress. I present the hypothesis that SLS evolved to expedite the death process, andrapidly remove from the population unfit parasites that, by elimination via SLS, causeminimal damage to the parasite population.