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Puf3 Participates in Ribosomal Biogenesis in Malaria Parasites Xiaoying Liang1, Kevin J

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Puf3 Participates in Ribosomal Biogenesis in Malaria Parasites Xiaoying Liang1, Kevin J © 2018. Published by The Company of Biologists Ltd | Journal of Cell Science (2018) 131, jcs212597. doi:10.1242/jcs.212597 RESEARCH ARTICLE Puf3 participates in ribosomal biogenesis in malaria parasites Xiaoying Liang1, Kevin J. Hart2, Gang Dong3, Faiza A. Siddiqui1, Aswathy Sebastian4, Xiaolian Li1, Istvan Albert4, Jun Miao1, Scott E. Lindner2 and Liwang Cui1,* ABSTRACT of Puf-encoding genes varies. Drosophila has only one Puf gene, In this study, we characterized the Puf family gene member Puf3 in the whereas 26 and 19 Puf-like genes have been found in the malaria parasites Plasmodium falciparum and Plasmodium yoelii. Arabidopsis and rice genomes, respectively (Tam et al., 2010). Secondary structure prediction suggested that the RNA-binding Puf members have diverse functions during development of domains of the Puf3 proteins consisted of 11 pumilio repeats that eukaryotic organisms. Puf members share a highly conserved were similar to those in the human Puf-A (also known as PUM3) and RNA-binding domain (RBD), which mostly consists of eight ∼ Saccharomyces cerevisiae Puf6 proteins, which are involved in imperfect tandem repeats of 36 amino acids, termed the Pum ribosome biogenesis. Neither P. falciparum (Pf)Puf3 nor P. yoelii repeats (Zamore et al., 1997; Zhang et al., 1997). (Py)Puf3 could be genetically disrupted, suggesting they may be Recent structural and functional studies have revealed three essential for the intraerythrocytic developmental cycle. Cellular distinct subfamilies within the Puf family proteins. Classical Puf fractionation of PfPuf3 in the asexual stages revealed preferential members contain eight Pum repeats organized in a crescent shape, partitioning to the nuclear fraction, consistent with nuclear localization of with the concave surface recognizing specific single-stranded RNA PfPuf3::GFP and PyPuf3::GFP as detected by immunofluorescence. sequences. These classical Puf proteins are predominantly localized Furthermore, PfPuf3 colocalized with the nucleolar marker PfNop1, within the cytoplasm of the cell, which is consistent with their roles demonstrating that PfPuf3 is a nucleolar protein in the asexual stages. in translational repression or activation of mRNAs (Archer et al., We found, however, that PyPuf3 changed its localization from being 2009; Gu et al., 2004; Lublin and Evans, 2007; Macdonald, 1992; nucleolar to being present in cytosolic puncta in the mosquito and liver Moore et al., 2003; Zhang et al., 1997). Classical Puf members stages, which may reflect alternative functions in these stages. Affinity perform a wide range of functions. In D. melanogaster, binding of purification of molecules that associated with a PTP-tagged variant of Pum to the Nanos response element (NRE) in the maternal PfPuf3 revealed 31 proteins associated with the 60S ribosome, and an hunchback mRNA determines abdominal formation by repressing enrichment of 28S rRNA and internal transcribed spacer 2 sequences. its translation (Murata and Wharton, 1995; Wharton et al., 1998; Taken together, these results suggest an essential function for PfPuf3 in Wharton and Struhl, 1991). In C. elegans, the Puf proteins FBF-1 ribosomal biogenesis. and FBF-2 were originally identified by their ability to bind regulatory elements in the 3′ UTR of fem-3 mRNA and repress its KEY WORDS: Plasmodium, Translational regulation, Puf protein, translation (Zhang et al., 1997), which is required for the switch RNA-binding protein, Ribosomal biogenesis from spermatogenesis to oogenesis in hermaphrodites (Ahringer and Kimble, 1991; Hodgkin, 1986). In addition, the FBF proteins INTRODUCTION were also reported to bind to and activate the translation of the target Translational control of gene expression plays an important role mRNA egl-4, which is important for adaptation to odors (Kaye during the development of eukaryotes. This regulation is often et al., 2009). In the budding yeast Saccharomyces cerevisiae, the mediated by cis-acting elements in the 3′ untranslated region (UTR) Puf protein Puf3p represses expression of the cox17 mRNA, of the mRNA. Binding of specific regulators to these cis elements promoting its deadenylation and subsequent decay (García- activates or represses translation of the mRNAs (Gray and Wickens, Rodríguez et al., 2007; Jackson et al., 2004; Olivas and Parker, 1998; Waters et al., 1989). One of these well-characterized 2000), while Puf5p and Puf6p have been shown to control mating regulators is the Puf family of RNA-binding proteins (RBPs), type switching by regulating the expression of the ho gene which were named after the two founding members, Pumilio (Pum) (Goldstrohm et al., 2006; Gu et al., 2004; Tadauchi et al., 2001). in Drosophila melanogaster and fem-3 binding factor (FBF) in Another subfamily of Puf proteins is represented by the human Caenorhabditis elegans (Zamore et al., 1997; Zhang et al., 1997). Puf-A (also known as PUM3) and S. cerevisiae Puf6 proteins (Li Members from this family represent a highly conserved group of et al., 2009; Qiu et al., 2014). Crystal structures of Puf-A and Puf6 RBPs present in many eukaryotic organisms including animals, revealed 11 Pum repeats that are arranged in an ‘L-like’ shape, with plants, fungi and protists. In different model organisms, the number the concave surfaces of the N- and C-terminal subdomains binding single- or double-stranded nucleic acids without apparent sequence specificity (Qiu et al., 2014). Both proteins primarily adopt a 1Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA. 2Department of Biochemistry and Molecular Biology, Center for nucleolar localization, and are involved in biogenesis of the 60S Malaria Research, Pennsylvania State University, University Park, PA 16802, USA. ribosome (Chang et al., 2011; Li et al., 2009; Qiu et al., 2014). A 3Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical closer look at Puf6 revealed that this protein is required for pre- University of Vienna, 1030 Vienna, Austria. 4Bioinformatics Consulting Center, Pennsylvania State University, University Park, Pennsylvania 16802, USA. rRNA processing and 60S ribosome export, and it also facilitates loading of the ribosome protein Rpl43 (Yang et al., 2016). *Author for correspondence ([email protected]) Moreover, S. cerevisiae Puf6 is also found in the cytoplasm, L.C., 0000-0002-8338-1974 where it acts as a translational repressor of the ash1 mRNA and is required for the asymmetric localization of ash1 to the bud tip of the Received 26 October 2017; Accepted 16 February 2018 daughter cell (Gu et al., 2004). Whereas human Puf-A appears to be Journal of Cell Science 1 RESEARCH ARTICLE Journal of Cell Science (2018) 131, jcs212597. doi:10.1242/jcs.212597 important for tumorigenesis (Fan et al., 2013), knockdown of Puf-A is a member of the Puf-A/Puf6 subfamily and may participate in in zebrafish results in abnormal eye development and primordial ribosomal biogenesis in Plasmodium parasites. germ cell migration (Kuo et al., 2009). The third Puf subfamily is represented by S. cerevisiae Nop9, a RESULTS nucleolar protein that is essential for 40S ribosome biogenesis PfPuf3 shows higher similarity to the Puf-A subfamily than (Thomson et al., 2007). Recently, structural and functional analyses the classical Puf subfamily showed that Nop9 contains 11 Pum repeats and forms a ‘C-shaped’ A search of the PlasmoDB database using the Pumilio Puf domain structure (Zhang et al., 2016). Consistent with its role in processing identified another putative Puf gene (PF3D7_0621300) in the the 20S pre-rRNA to produce mature 18S rRNA, Nop9 recognizes P. falciparum genome, which we here call PfPuf3.ThePfPuf3 the base of the internal transcribed spacer (ITS) 1 RNA stem loop, open reading frame is 2382 bp, located on chromosome 6 and which prevents premature cleavage of the 20S pre-rRNA by Nob1 in contains no introns. PfPuf3 encodes a protein of 793 amino acids (aa) the nucleolus (Zhang et al., 2016). In Arabidopsis, APUM23, a with a predicted molecular mass of ∼94.3 kDa. The predicted Puf Nop9 subfamily member, is involved in pre-rRNA processing, and RBD of PfPuf3 is located from aa 166 to 526. Whereas the amino acid disruption of apum23 leads to the accumulation of 35S pre-rRNA sequences of the Puf RBD of PfPuf1 and PfPuf2 are 41 and 58% and unprocessed 18S and 5.8S rRNA precursors without affecting identical to the respective sequences of the Pum RBDs from the steady-state levels of the mature rRNAs (Abbasi et al., 2010, Drosophila melanogaster (Cui et al., 2002), PfPuf3 and Pum RBD 2011). Consistent with its role in ribosomal biogenesis, apum23 only have 15% amino acid identity overall. Like the Puf1 and Puf2 disruption results in an abnormal growth phenotype reminiscent of genes, Puf3 is highly conserved in Plasmodium spp. and a Puf3 that in ribosomal protein gene mutants. In the protozoan parasite ortholog is present in the genome of each sequenced Plasmodium Trypanosoma brucei, two nucleolar Puf proteins, T. brucei species (Fig. 1A). The full-length PfPuf3 sequence shares 45% amino (Tb)PUF7 and TbPUF10, may also be Nop9 subfamily members, acid identity with the orthologous PyPuf3 (PY17X_1121600) and their knockdown (through RNAi) affects rRNA processing, (Fig. S1A). A search for homologous structures based on the leading to slow-growth phenotypes (Droll et al., 2010; Schumann PfPuf3 primary sequence by using NCBI Blastp identified Homo Burkard et al., 2013). These examples have illustrated somewhat sapiens (Hs)Puf-A as the most similar structure in the Protein Data convergent functions for the Puf-A/Puf6 and Nop9 subfamilies of Bank (Qiu et al., 2014). However, sequence alignment showed that the Puf proteins in pre-rRNA processing and ribosomal biogenesis. PfPuf3 shares only 15.1% amino acid identity in the 511-residue (aa It has been increasingly recognized that translational regulation 156–774) fragment that aligned with HsPuf-A (Fig. S1B). Within the plays essential roles in the development of malaria parasites, aligned region, PfPuf3 has a long insertion spanning aa 573–687 especially during developmental stage transitions (Cui et al., 2015).
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