Sir3 helps telomeres stick together

Mutant phagosomes bite off more than they can chew A kbar et al. reveal that the fl y homologue of a gene mutated in human disease encodes a protein required for phagosome matura-tion and digestion of pathogens. The HOPS complex is a multi-subunit tethering factor that regulates vacuole fusion in budding yeast. Metazoans express two versions of the HOPS subunits Vps16p and Vps33p. Vps16A and Vps33A promote the delivery of endosomes and autophagosomes to lysosomes in fl ies. The function of Vps16B and Vps33B is less clear, but mutations in the human ho-mologues of these proteins cause a fatal multisystem disease called arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome. Akbar et al. generated fl ies lacking Vps16B and found that they were surprisingly healthy and had no defects in autophagosome or endocytic traffi cking. Knowing that ARC syndrome patients are susceptible to recurrent bacterial infections, however, the researchers injected the fl ies with E. coli and found that Vps16B mutants died much faster than wild-type strains. Mutant fl y macrophages engulfed the bacteria normally but failed to digest them, as phagosomes failed to fully mature and fuse with lysosomes. This caused the bacteria to accumulate in intermediate phagocytic compartments, prompting Akbar et al. to name the Drosophila Vps16B gene full-of-bacteria. Similar effects were seen after knocking down Vps33B in fl ies. It remains to be seen whether human Vps16B and Vps33B also control phagosome maturation and whether defects in this process account for other symptoms of ARC syndrome. Senior author Helmut Krämer now wants to investigate how the different HOPS subunit homologues contribute to distinct traffi cking pathways. Sir3 helps telomeres stick together T he silencing factor Sir3 clusters together the ends of yeast chromosomes , Ruault et al. report. Yeast telomeres gather into distinct subcompartments near the nuclear periphery, thereby concentrating the gene-silencing factors that bind them. This improves the silencing of genes lying near chromosome ends, while avoiding inappropriate repression of genes located elsewhere in the genome. Silencing may in turn regulate clustering, because deleting components of the Sir2–Sir3–Sir4 silencing complex disrupts telomere organization. Ruault et al. overexpressed individual subunits of the Sir2– Sir3–Sir4 complex to investigate which of them was responsible for aggregating telomeres. Sir3 overexpression bunched telomeres into larger foci than those found in wild-type cells and repressed genes in subtelomeric regions more stably. Silencing wasn't required for telomere clustering to occur, however. Overexpression of a …