Academic journal article Genetics

V-ATPase V^sub 1^ Sector Is Required for Corpse Clearance and Neurotransmission in Caenorhabditis Elegans

Academic journal article Genetics

V-ATPase V^sub 1^ Sector Is Required for Corpse Clearance and Neurotransmission in Caenorhabditis Elegans

Article excerpt

ABSTRACT The vacuolar-type ATPase (V-ATPase) is a proton pump composed of two sectors, the cytoplasmic V^sub 1^ sector that catalyzes ATP hydrolysis and the transmembrane V^sub o^ sector responsible for proton translocation. The transmembrane V^sub o^ complex directs the complex to different membranes, but also has been proposed to have roles independent of the V^sub 1^ sector. However, the roles of the V^sub 1^ sector have not been well characterized. In the nematode Caenorhabditis elegans there are two V^sub 1^ B-subunit genes; one of them, vha- 12, is on the X chromosome, whereas spe-5 is on an autosome. vha-12 is broadly expressed in adults, and homozygotes for a weak allele in vha-12 are viable but are uncoordinated due to decreased neurotransmission. Analysis of a null mutation demonstrates that vha-12 is not required for oogenesis or spermatogenesis in the adult germ line, but it is required maternally for early embryonic development. Zygotic expression begins during embryonic morphogenesis, and homozygous null mutants arrest at the twofold stage. These mutant embryos exhibit a defect in the clearance of apoptotic cell corpses in vha-12 null mutants. These observations indicate that the V^sub 1^ sector, in addition to the V^sub o^ sector, is required in exocytic and endocytic pathways.

ONE role of vacuolar-type proton ATPases (V-ATPase) is to acidify organelles in secretory and endocytic pathways (Mellman et al. 1986; Futai et al. 2000; Forgac 2007). The V-ATPase is composed of two substructures: a catalytic domain of eight different subunits called the V1 sector and a membrane-anchored set of subunits called the Vo sector (Figure 1A). Both sectors are required for acidification of cellular organelles; however, genetic analysis suggests that the Vo domain may have an additional role in promoting membrane fusion (Peters et al. 2001; Hiesinger et al. 2005; Liégeois et al. 2006; Sun-Wada et al. 2006; Peri and Nüsslein-Volhard 2008; Di Giovanni et al. 2010; Williamson et al. 2010; Strasser et al. 2011). To distinguish the roles of acidification and potential additional roles of the V-ATPase, it is particularly important to identify the functions of the catalytic V1 sector.

The differential expression and localization of specialized V1 sector subunits suggest that the proton pump could be adopted for different purposes (Toei et al. 2010). For example, in mammals different B isoforms of the V1 sector are localized to either the cell surface or internal membranes. The B1 isoform is localized to the surface of specialized kidney, inner ear, and vas deferens epithelial cells where it pumps protons into the extracellular space, whereas the B2 subunit is typically associated with endosomes and pumps protons into the lumen of organelles (Brown et al. 2009). Consistent with the epithelial localization of B1 subunits, mutations in the B1 surface isoform are linked to renal tubule acidosis and deafness in humans (Karet et al. 1999; Stover et al. 2002; Hahn et al. 2003; Vargas-Poussou et al. 2006; Gil et al. 2007; Fuster et al. 2008).

However, a rigid B-subunit specialization does not seem to be common in all animals. The mouse genome also encodes two B subunits. But unlike humans, mutation of the apical B1 subunit in mice does not result in deafness or kidney dysfunction (Dou et al. 2003; Finberg et al. 2005). The B2 subunit, normally localized to endosomes, can partially compensate for the loss of B1 subunits (Paunescu et al. 2007), suggesting that B-subunit specialization is not universal. Only one B-subunit gene is encoded in the Drosophila genome, suggesting that there is no specialization of subunits (Du et al. 2006). The fly VHA55 protein is localized on internal membranes as well as on the apical surface on the kidney-like Malpighian tubules, consistent with acidification of organelles and proton extrusion (Du et al. 2006). In contrast to B1 mutations in mice, mutations in vha55 are larval lethal (Davies et al. …

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