Novel LOTUS-domain proteins are organizational hubs that recruit C. elegans Vasa to germ granules

  1. Patricia Giselle Cipriani
  2. Olivia Bay
  3. John Zinno
  4. Michelle Gutwein
  5. Hin Hark Gan
  6. Vinay K Mayya
  7. George Chung
  8. Jia-Xuan Chen
  9. Hala Fahs
  10. Yu Guan
  11. Thomas F Duchaine
  12. Matthias Selbach
  13. Fabio Piano
  14. Kristin C Gunsalus  Is a corresponding author
  1. New York University, United States
  2. McGill University, Canada
  3. Max Delbrück Center for Molecular Medicine, Germany
  4. New York University Abu Dhabi, United Arab Emirates

Abstract

We describe MIP-1 and MIP-2, novel paralogous C. elegans germ granule components that interact with the intrinsically disordered MEG-3 protein. These proteins promote P granule condensation, form granules independently of MEG-3 in the postembryonic germ line, and balance each other in regulating P granule growth and localization. MIP-1 and MIP-2 each contain two LOTUS domains and intrinsically disordered regions and form homo- and heterodimers. They bind and anchor the Vasa homolog GLH-1 within P granules and are jointly required for coalescence of MEG-3, GLH-1, and PGL proteins. Animals lacking MIP-1 and MIP-2 show temperature-sensitive embryonic lethality, sterility, and mortal germ lines. Germline phenotypes include defects in stem cell self-renewal, meiotic progression, and gamete differentiation. We propose that these proteins serve as scaffolds and organizing centers for ribonucleoprotein networks within P granules that help recruit and balance essential RNA processing machinery to regulate key developmental transitions in the germ line.

Data availability

All mass spectrometry raw data have been deposited to the PRIDE repository with the dataset identifier PXD012852. All other data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2A-C; Figure 2-figure supplement 2; Figure 6A,B; Figure 8E; Figure 9B; Figure 9-figure supplement 1; Figure 10C.

The following data sets were generated

Article and author information

Author details

  1. Patricia Giselle Cipriani

    Center for Genomics and Systems Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Olivia Bay

    Center for Genomics and Systems Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. John Zinno

    Center for Genomics and Systems Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Michelle Gutwein

    Center for Genomics and Systems Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Hin Hark Gan

    Center for Genomics and Systems Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Vinay K Mayya

    Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. George Chung

    Center for Genomics and Systems Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jia-Xuan Chen

    None, Max Delbrück Center for Molecular Medicine, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Hala Fahs

    Center for Genomics and Systems Biology, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
    Competing interests
    The authors declare that no competing interests exist.
  10. Yu Guan

    Center for Genomics and Systems Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Thomas F Duchaine

    Goodman Cancer Research Center, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  12. Matthias Selbach

    Department of Protein Dynamics, Max Delbrück Center for Molecular Medicine, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Fabio Piano

    Department of Biology and Center for Genomics and Systems Biology, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Kristin C Gunsalus

    Center for Genomics and Systems Biology, New York University, New York, United States
    For correspondence
    kcg1@nyu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9769-4624

Funding

New York University Abu Dhabi (ADPHG CGSB)

  • Patricia Giselle Cipriani
  • Hala Fahs
  • Fabio Piano
  • Kristin C Gunsalus

New York University Abu Dhabi

  • Patricia Giselle Cipriani
  • Olivia Bay
  • John Zinno
  • Michelle Gutwein
  • Hin Hark Gan
  • George Chung
  • Fabio Piano
  • Kristin C Gunsalus

Canadian Institutes of Health Research (MOP 123352)

  • Vinay K Mayya
  • Thomas F Duchaine

Charlotte and Leo Karassik Foundation

  • Vinay K Mayya

Bundesministerium für Bildung und Forschung (0315362)

  • Jia-Xuan Chen

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

Reviewing Editor

  1. Michael Buszczak, University of Texas Southwestern Medical Center, United States

Version history

  1. Received: July 8, 2020
  2. Accepted: June 27, 2021
  3. Accepted Manuscript published: July 5, 2021 (version 1)
  4. Version of Record published: August 3, 2021 (version 2)

Copyright

© 2021, Cipriani 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

  • 2,427
    Page views
  • 219
    Downloads
  • 8
    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. Patricia Giselle Cipriani
  2. Olivia Bay
  3. John Zinno
  4. Michelle Gutwein
  5. Hin Hark Gan
  6. Vinay K Mayya
  7. George Chung
  8. Jia-Xuan Chen
  9. Hala Fahs
  10. Yu Guan
  11. Thomas F Duchaine
  12. Matthias Selbach
  13. Fabio Piano
  14. Kristin C Gunsalus
(2021)
Novel LOTUS-domain proteins are organizational hubs that recruit C. elegans Vasa to germ granules
eLife 10:e60833.
https://doi.org/10.7554/eLife.60833

Share this article

https://doi.org/10.7554/eLife.60833

Further reading

    1. Cell Biology
    2. Medicine
    Chun Wang, Khushpreet Kaur ... Gabriel Mbalaviele
    Research Article

    Chemotherapy is a widely used treatment for a variety of solid and hematological malignancies. Despite its success in improving the survival rate of cancer patients, chemotherapy causes significant toxicity to multiple organs, including the skeleton, but the underlying mechanisms have yet to be elucidated. Using tumor-free mouse models, which are commonly used to assess direct off-target effects of anti-neoplastic therapies, we found that doxorubicin caused massive bone loss in wild-type mice, a phenotype associated with increased number of osteoclasts, leukopenia, elevated serum levels of danger-associated molecular patterns (DAMPs; e.g. cell-free DNA and ATP) and cytokines (e.g. IL-1β and IL-18). Accordingly, doxorubicin activated the absent in melanoma (AIM2) and NLR family pyrin domain containing 3 (NLRP3) inflammasomes in macrophages and neutrophils, causing inflammatory cell death pyroptosis and NETosis, which correlated with its leukopenic effects. Moreover, the effects of this chemotherapeutic agent on cytokine secretion, cell demise, and bone loss were attenuated to various extent in conditions of AIM2 and/or NLRP3 insufficiency. Thus, we found that inflammasomes are key players in bone loss caused by doxorubicin, a finding that may inspire the development of a tailored adjuvant therapy that preserves the quality of this tissue in patients treated with this class of drugs.

    1. Cell Biology
    Zeina Salloum, Kristin Dauner ... Xiaohui Zha
    Research Article

    Stains are known to be anti-inflammatory, but the mechanism remains poorly understood. Here we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the ATP synthase in the inner mitochondrial membrane (IMM) and changes the proton gradient in the mitochondria. This activates NFkB and Jmjd3 expression to remove the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus LPS (M1), both macrophages treated with statins in vitro or isolated from statin-treated mice in vivo, express lower levels pro-inflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.