1. Cell Biology
  2. Neuroscience
Download icon

The Insulin/IGF signaling cascade modulates SUMOylation to regulate aging and proteostasis in C. elegans

Research Article
  • Cited 3
  • Views 2,029
  • Annotations
Cite this article as: eLife 2018;7:e38635 doi: 10.7554/eLife.38635

Abstract

Although aging-regulating pathways were discovered a few decades ago, it is not entirely clear how their activities are orchestrated, to govern lifespan and proteostasis at the organismal level. Here we utilized the nematode Caenorhabditis elegans to examine whether the alteration of aging, by reducing the activity of the Insulin/IGF signaling (IIS) cascade, affects protein SUMOylation. We found that IIS activity promotes the SUMOylation of the germline protein, CAR-1, thereby shortening lifespan and impairing proteostasis. In contrast, the expression of mutated CAR-1, that cannot be SUMOylated at residue 185, extends lifespan and enhances proteostasis. A mechanistic analysis indicated that CAR-1 mediates its aging-altering functions, at least partially, through the notch-like receptor glp-1. Our findings unveil a novel regulatory axis in which SUMOylation is utilized to integrate the aging-controlling functions of the IIS and of the germline and provide new insights into the roles of SUMOylation in the regulation of organismal aging.

Data availability

Mass Spectrometry data has been deposited at http://www.ebi.ac.uk/pride (Project accession: PXD010011).

The following data sets were generated

Article and author information

Author details

  1. Lorna Moll

    Department of Biochemistry and Molecular Biology, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Noa Roitenberg

    Department of Biochemistry and Molecular Biology, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Michal Bejerano-Sagie

    Department of Biochemistry and Molecular Biology, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Hana Boocholez

    Department of Biochemistry and Molecular Biology, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Filipa Carvalhal Marques

    Department of Biochemistry and Molecular Biology, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Yuli Volovik

    Department of Biochemistry and Molecular Biology, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  7. Tayir Elami

    Department of Biochemistry and Molecular Biology, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  8. Atif Ahmed Siddiqui

    Department of Biochemistry and Molecular Biology, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  9. Danielle Grushko

    Department of Biochemistry and Molecular Biology, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  10. Adi Biram

    Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6169-9861
  11. Bar Lampert

    Department of Genetics, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  12. Hana Achache

    Department of Genetics, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  13. Tommer Ravid

    Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  14. Yonatan B Tzur

    Department of Genetics, Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
    Competing interests
    The authors declare that no competing interests exist.
  15. Ehud Cohen

    Department of Biochemistry and Molecular Biology, The Hebrew University of Jerusalem, Jerusalem, Israel
    For correspondence
    ehudc@ekmd.huji.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5552-7086

Funding

Israel Science Foundation (EC 981/16)

  • Hana Boocholez
  • Danielle Grushko
  • Ehud Cohen

Israel Science Foundation (YBT 2090/15)

  • Bar Lampert
  • Yonatan B Tzur

Israel Science Foundation (YBT 1283/15)

  • Bar Lampert
  • Yonatan B Tzur

European Research Council (EC 281010)

  • Lorna Moll
  • Noa Roitenberg
  • Michal Bejerano-Sagie
  • Filipa Carvalhal Marques
  • Yuli Volovik
  • Tayir Elami
  • Danielle Grushko
  • Ehud Cohen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Inna Slutsky, Tel Aviv University, Israel

Publication history

  1. Received: May 24, 2018
  2. Accepted: November 6, 2018
  3. Accepted Manuscript published: November 7, 2018 (version 1)
  4. Version of Record published: December 3, 2018 (version 2)

Copyright

© 2018, Moll et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 2,029
    Page views
  • 408
    Downloads
  • 3
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Zdravka Daneva et al.
    Research Article Updated

    Pannexin 1 (Panx1), an ATP-efflux pathway, has been linked with inflammation in pulmonary capillaries. However, the physiological roles of endothelial Panx1 in the pulmonary vasculature are unknown. Endothelial transient receptor potential vanilloid 4 (TRPV4) channels lower pulmonary artery (PA) contractility and exogenous ATP activates endothelial TRPV4 channels. We hypothesized that endothelial Panx1–ATP–TRPV4 channel signaling promotes vasodilation and lowers pulmonary arterial pressure (PAP). Endothelial, but not smooth muscle, knockout of Panx1 increased PA contractility and raised PAP in mice. Flow/shear stress increased ATP efflux through endothelial Panx1 in PAs. Panx1-effluxed extracellular ATP signaled through purinergic P2Y2 receptor (P2Y2R) to activate protein kinase Cα (PKCα), which in turn activated endothelial TRPV4 channels. Finally, caveolin-1 provided a signaling scaffold for endothelial Panx1, P2Y2R, PKCα, and TRPV4 channels in PAs, promoting their spatial proximity and enabling signaling interactions. These results indicate that endothelial Panx1–P2Y2R–TRPV4 channel signaling, facilitated by caveolin-1, reduces PA contractility and lowers PAP in mice.

    1. Cell Biology
    Adria Razzauti, Patrick FM Laurent
    Research Article

    Cilia are sensory organelles protruding from cell surfaces. Release of Extracellular Vesicles (EVs) from cilia was previously observed in mammals, Chlamydomonas, and in male C. elegans. Using the EV marker TSP-6 (an ortholog of mammalian CD9) and other ciliary receptors, we show that EVs are formed from ciliated sensory neurons in C. elegans hermaphrodites. Release of EVs is observed from two ciliary locations: the cilia tip and/or Periciliary Membrane Compartment (PCMC). Outward budding of EVs from the cilia tip leads to their release into the environment. EVs budding from the PCMC are concomitantly phagocytosed by the associated glial cells. To maintain cilia composition, a tight regulation of cargo import and removal is achieved by the action of Intra-Flagellar Transport (IFT). Unbalanced IFT due to cargo overexpression or mutations in the IFT machinery leads to local accumulation of ciliary proteins. Disposal of excess ciliary proteins via EVs reduces their local accumulation and exports them to the environment and/or to the glia associated to these ciliated neurons. We suggest that EV budding from cilia subcompartments acts as a safeguard mechanism to remove deleterious excess of ciliary material.