All Publications

  • ALIX Is a Lys63-Specific Polyubiquitin Binding Protein that Functions in Retrovirus Budding DEVELOPMENTAL CELL Dowlatshahi, D. P., Sandrin, V., Vivona, S., Shaler, T. A., Kaiser, S. E., Melandri, F., Sundquist, W. I., Kopito, R. R. 2012; 23 (6): 1247-1254


    The diversity of ubiquitin (Ub)-dependent signaling is attributed to the ability of this small protein to form different types of covalently linked polyUb chains and to the existence of Ub binding proteins that interpret this molecular syntax. We used affinity capture/mass spectrometry to identify ALIX, a component of the ESCRT pathway, as a Ub binding protein. We report that the V domain of ALIX binds directly and selectively to K63-linked polyUb chains, exhibiting a strong preference for chains composed of more than three Ub. Sequence analysis identified two potential Ub binding sites on a single α-helical surface within the coiled-coil region of the V domain. Mutation of these putative Ub binding sites inhibited polyUb binding to the isolated V domain in vitro and impaired budding of lentiviruses. These data reveal an important role for K63 polyUb binding by ALIX in retroviral release.

    View details for DOI 10.1016/j.devcel.2012.10.023

    View details for Web of Science ID 000312429200020

    View details for PubMedID 23201121

    View details for PubMedCentralID PMC3522770

  • An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C-elegans CURRENT BIOLOGY Greer, E. L., Dowlatshahi, D., Banko, M. R., Villen, J., Hoang, K., Blanchard, D., Gygi, S. P., Brunet, A. 2007; 17 (19): 1646-1656


    Dietary restriction (DR) is the most effective environmental intervention to extend lifespan in a wide range of species. However, the molecular mechanisms underlying the benefits of DR on longevity are still poorly characterized. AMP-activated protein kinase (AMPK) is activated by a decrease in energy levels, raising the possibility that AMPK might mediate lifespan extension by DR.By using a novel DR assay that we developed and validated in C. elegans, we find that AMPK is required for this DR method to extend lifespan and delay age-dependent decline. We find that AMPK exerts its effects in part via the FOXO transcription factor DAF-16. FOXO/DAF-16 is necessary for the beneficial effects of this DR method on lifespan. Expression of an active version of AMPK in worms increases stress resistance and extends longevity in a FOXO/DAF-16-dependent manner. Lastly, we find that AMPK activates FOXO/DAF-16-dependent transcription and phosphorylates FOXO/DAF-16 at previously unidentified sites, suggesting a possible direct mechanism of regulation of FOXO/DAF-16 by AMPK.Our study shows that an energy-sensing AMPK-FOXO pathway mediates the lifespan extension induced by a novel method of dietary restriction in C. elegans.

    View details for DOI 10.1016/j.cub.2007.08.047

    View details for Web of Science ID 000250125200023

    View details for PubMedID 17900900

    View details for PubMedCentralID PMC2185793