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

Version 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

  • 2,382
    Page views
  • 449
    Downloads
  • 14
    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)

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

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

  1. Lorna Moll
  2. Noa Roitenberg
  3. Michal Bejerano-Sagie
  4. Hana Boocholez
  5. Filipa Carvalhal Marques
  6. Yuli Volovik
  7. Tayir Elami
  8. Atif Ahmed Siddiqui
  9. Danielle Grushko
  10. Adi Biram
  11. Bar Lampert
  12. Hana Achache
  13. Tommer Ravid
  14. Yonatan B Tzur
  15. Ehud Cohen
(2018)
The Insulin/IGF signaling cascade modulates SUMOylation to regulate aging and proteostasis in C. elegans
eLife 7:e38635.
https://doi.org/10.7554/eLife.38635

Share this article

https://doi.org/10.7554/eLife.38635

Further reading

    1. Cell Biology
    Wan-ping Yang, Mei-qi Li ... Qian-qian Luo
    Research Article

    High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen’s ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.

    1. Cell Biology
    Jurgen Denecke
    Insight

    Mapping proteins in and associated with the Golgi apparatus reveals how this cellular compartment emerges in budding yeast and progresses over time.