Academic journal article Genetics

Regulation of Ribosome Biogenesis by Nucleostemin 3 Promotes Local and Systemic Growth in Drosophila

Academic journal article Genetics

Regulation of Ribosome Biogenesis by Nucleostemin 3 Promotes Local and Systemic Growth in Drosophila

Article excerpt

ABSTRACT Nucleostemin 3 (NS3) is an evolutionarily conserved protein with profound roles in cell growth and viability. Here we analyze cell-autonomous and non-cell-autonomous growth control roles of NS3 in Drosophila and demonstrate its GTPase activity using genetic and biochemical assays. Two null alleles of ns3, and RNAi, demonstrate the necessity of NS3 for cell autonomous growth. A hypomorphic allele highlights the hypersensitivity of neurons to lowered NS3 function. We propose that NS3 is the functional ortholog of yeast and human Lsg1, which promotes release of the nuclear export adapter from the large ribosomal subunit. Release of the adapter and its recycling to the nucleus are essential for sustained production of ribosomes. The ribosome biogenesis role of NS3 is essential for proper rates of translation in all tissues and is necessary for functions of growth-promoting neurons.

THE rate and fidelity of protein synthesis in a cell depend upon the proper assembly of the ribosome. Ribosome biogenesis begins in the nucleolus with the synthesis of ribosomal RNA (rRNA) and culminates in the creation of a fully functional ribosome competent to initiate protein synthesis in the cytoplasm. This process is impressively intricate, requiring ~200 factors acting at various levels. Major ribosome biogenesis steps include directing rRNA post-transcriptional modification, 90S cleavage, folding/ assembly of the small (40S) and large (60S) ribosomal subunits, and proper transport from the nucleus to cytoplasm where final maturation occurs (Zemp and Kutay 2007; Henras et al. 2008; Staley and Woolford 2009; Strunk and Karbstein 2009; Panse and Johnson 2010).

Export of pre-ribosomal subunits from the nucleus to the cytoplasm requires movement through the nuclear pore complex (Hurt et al. 1999; Moy and Silver 1999; Stage- Zimmermann et al. 2000; Seiser et al. 2006). The pre-60S subunit achieves nuclear export by recruiting nuclear export factors, including the nuclear export signal (NES)-bearing protein Nmd3 (Ho et al. 2000; Gadal et al. 2001). Equally essential is recycling of Nmd3 from the cytoplasm back to the nucleus for subsequent rounds of pre-60S export. The release of Nmd3 appears to be the last step of a highly ordered pathway of ribosome maturation in the cytoplasm (Lo et al. 2010). Studies in Saccharomyces cerevisiae implicated RpL10p and Lsg1p as factors critical for Nmd3 recycling. Loss of either RpL10p or Lsg1p caused accumulation of Nmd3 in the cytoplasm, which precluded its ability to return to the nucleus for additional rounds of pre-60S export (Hedges et al. 2005). Thus, the loss of Nmd3p, RpL10p, or Lsg1p through mutation causes 60S subunit deficiency in the cytoplasm.

In Drosophila, a well-known class of mutations, called Minutes affects ribosome assembly. Minutes have delayed development and small or "minute" bristles; mutations affecting 66 of the 88 predicted ribosomal proteins have this phenotype (Marygold et al. 2007). The first Minute gene was discovered by Calvin Bridges and T. H. Morgan in 1919 (Bridges and Morgan 1923). This allele of RpS8 was the founding member of what came to be a large class of genes that are often haplo-insufficient. Later, with the advent of molecular biology, it became clear that most Minute genes code for ribosomal proteins. The conclusion was that the normal rate of progression through larval development and normal bristle synthesis are highly sensitive to protein synthesis rates (Lambertsson 1998).

Loss-of-function alleles for different ribosomal protein genes can have distinctive phenotypes in addition to the shared classical Minute phenotypes. For instance, loss of RpS6, a small subunit protein, causes a counterintuitive phenotype: extensive larval overgrowth (Lin et al. 2011). Studies to determine which tissues normally require RpS6 to restrict growth showed that prothoracic glands of RpS6 mutants do not function properly. The consequent lower level of the hormone ecdysone, which promotes larval developmental progression and molts, extends the period of larval development and feeding. …

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