The mechanism of SLS. In trypanosomes all mRNA are trans -spliced. In this process, the exon or spliced leader is donated to the mRNA from a small RNA, the spliced leader RNA. The SL RNA is transcribed and assembled in a distinct nuclear site that was termed the SL factory , where the SL RNA is transcribed, modified and assembles with its binding protein. Under stress that perturbs the ER homeostasis such as blocking translocation of proteins across the ER membrane (via RNAi silencing of SRP receptor, SEC61, or SEC63) or by prolonged exposure to chemicals such as DTT and 2DG or under drastic pH changes, the SLS pathway is induced. The hallmarks of SLS are shut-off in SL RNA transcription due to the inability of tSNA42 to bind to the SL RNA promoter, leading to the accumulation of the tSNAP42 in the nucleus. The shut-off of SL RNA transcription leads to marked reduction in mRNA production and to induction of apoptosis. One key kinase in this pathway is PK-3, a serine-threonine kinase that transmits the signal from the ER to the nucleus. Despite the fact that trans-splicing is inhibited during SLS, the level of certain mRNAs is increased. These mRNAs may lead the synthesis of proteins that are essential for executing SLS.