porting the hypothesis that PfSR1 is indeed an SR protein. However, while our results support the previous observation that PfSR1 shuttles between the nucleus and the cytoplasm during the IDC, we found some distinct differences in the patterns of cellular localization of PfSR1 compared with what was previously reported. First, we found that the nuclear location of PfSR1 at early ring stages is in a distinct punctuated pattern mainly at the nuclear periphery and is not equally spread all over the nucleus as previously shown. The pattern of sub-nuclear localization of PfSR1 in ring stages shown here is more similar to the sub-nuclear localization of SRSF1 which is found at distinct nuclear speckles. These speckles are 
believed to be sub-nuclear storage compartments for SR proteins and other splicing factors. In addition, while PfSR1 in the cytoplasm seems to be more evenly spread than in the nucleus, it is clear that its cytoplasmic location is Scutellarein restricted to region that are outside the food vacuole, while previously it was shown throughout the entire cytoplasm. These previous data were obtained using polyclonal antibodies raised against recombinant PfSR1. It is possible that IFAs using an epitope tagged PfSR1 have an advantage in getting better resolution for cellular localization as detected here. Our deletion analyses of the PfSR1 mutants lacking different domains have indicated that the RS domain of PfSR1 acts as NLS similar to the mammalian SRSF1. Interestingly, deletion of either of the RRM domains seems to have no effect on the cellular location of PfSR1. Some of the mammalian SR proteins, including SRSF1, shuttle continuously between the nucleus and the cytoplasm. This movement was found to be associated with phosphorylation of specific residues at the RS or RRM domains. One can hypothesize that phosphorylation of the RS domain of PfSR1 by PfSRPK1 influences it’s binding affinity for mRNA, and that this modification could also regulate its cellular localization and function in P. falciparum. The dynamic cellular localization of PfSR1 may reflect a functional transition of PfSR1 during the IDC, from mainly nuclear functions such as splicing PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19816210 and AS at early ring stages to additional roles that take place in cytoplasm in late stages and in gametocytes. In recent years there is mounting evidence that SR proteins in metazoans are involved in many other cellular processes. These include chromatin re-modeling, transcription, cell cycle progression, mRNA export, nonsense-mediated mRNA decay and translation . One cannot exclude that in addition to its role in splicing and AS shown here, PfSR1 may have other functions as indicated by its localization both to the nucleus and cytoplasm. Ectopic over-expression of pfsr1 caused strong inhibition of culture growth even at relatively low levels of gene over-expression, indicating that tight regulation of pfsr1 is essential for parasite proliferation in human RBCs. These results are supported by experiments showing that only low levels of overexpression of several SR proteins could be achieved in mammalian cells before they underwent apoptosis. In addition, reduced expression of SRSF1 was found to elicit genomic instability and apoptosis. The involvement of SR proteins in several of the basic cellular processes in living cells can explain why P. falciparum parasites tightly regulate pfsr1 so that even the low levels of over-expression obtained here caused significant growth inhibition. Interestingl
