1. Cell Biology
  2. Structural Biology and Molecular Biophysics

The KASH5 protein involved in meiotic chromosomal movements is a novel dynein activating adaptor

  1. Ritvija Agrawal
  2. John P Gillies
  3. Juliana L Zang
  4. Jingjing Zhang
  5. Sharon R Garrott
  6. Hiroki Shibuya  Is a corresponding author
  7. Jayakrishnan Nandakumar  Is a corresponding author
  8. Morgan E DeSantis  Is a corresponding author
  1. University of Michigan-Ann Arbor, United States
  2. University of Gothenburg, Sweden
https://doi.org/10.7554/eLife.78201
Share this article
Cite this article
  1. Ritvija Agrawal
  2. John P Gillies
  3. Juliana L Zang
  4. Jingjing Zhang
  5. Sharon R Garrott
  6. Hiroki Shibuya
  7. Jayakrishnan Nandakumar
  8. Morgan E DeSantis
(2022)
The KASH5 protein involved in meiotic chromosomal movements is a novel dynein activating adaptor
eLife 11:e78201.
https://doi.org/10.7554/eLife.78201
  2. Download BibTeX
  3. Download .RIS

Abstract

Dynein harnesses ATP hydrolysis to move cargo on microtubules in multiple biological contexts. Dynein meets a unique challenge in meiosis by moving chromosomes tethered to the nuclear envelope to facilitate homolog pairing essential for gametogenesis. Though processive dynein motility requires binding to an activating adaptor, the identity of the activating adaptor required for dynein to move meiotic chromosomes is unknown. We show that the meiosis-specific nuclear-envelope protein KASH5 is a dynein activating adaptor: KASH5 directly binds dynein using a mechanism conserved among activating adaptors and converts dynein into a processive motor. We map the dynein-binding surface of KASH5, identifying mutations that abrogate dynein binding in vitro and disrupt recruitment of the dynein machinery to the nuclear envelope in cultured cells and mouse spermatocytes in vivo. Our study identifies KASH5 as the first transmembrane dynein activating adaptor and provides molecular insights into how it activates dynein during meiosis.

Data availability

Source data for TIRF experiments in Figure 3-6 are found in the file "Agrawal_etal_Source data" and labeled appropriately.All custom macros written for this study (used in Figure 5) are available on GitHub (https://github.com/DeSantis-Lab/Nuclear_Envelope_Localization_Macros)

The following data sets were generated

Article and author information

Author details

  1. Ritvija Agrawal

    Department of Molecular, Cellular and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. John P Gillies

    Department of Molecular, Cellular and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Juliana L Zang

    Department of Molecular, Cellular and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5738-8355

  4. Jingjing Zhang

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.

  5. Sharon R Garrott

    Department of Molecular, Cellular and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Hiroki Shibuya

    Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
    For correspondence
    hiroki.shibuya@gu.se
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3400-0741

  7. Jayakrishnan Nandakumar

    Department of Molecular, Cellular and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States
    For correspondence
    jknanda@umich.edu
    Competing interests
    The authors declare that no competing interests exist.

  8. Morgan E DeSantis

    Department of Molecular, Cellular and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States
    For correspondence
    mdesant@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4096-8548

Funding

National Institutes of Health (R00-GM127757)

  • Morgan E DeSantis

National Institutes of Health (R01-GM120094)

  • Jayakrishnan Nandakumar

American Heart Association (RSG-17-037-01-DMC)

  • Jayakrishnan Nandakumar

European Research Council (StG-801659)

  • Hiroki Shibuya

Swedish Research Council (2018-03426)

  • Hiroki Shibuya

Knut och Alice Wallenbergs Stiftelse (KAW2019.0180)

  • Hiroki Shibuya

American Heart Association

  • Ritvija Agrawal

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

Ethics

Animal experimentation: All animal experiments were approved by and performed in compliance with the regulations at the University of Gothenburg Institutional Animal Care and Use Committee (#1316/18).

Copyright

© 2022, Agrawal 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

  • 1,840
    views
  • 456
    downloads
  • 24
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Ritvija Agrawal
  2. John P Gillies
  3. Juliana L Zang
  4. Jingjing Zhang
  5. Sharon R Garrott
  6. Hiroki Shibuya
  7. Jayakrishnan Nandakumar
  8. Morgan E DeSantis
(2022)
The KASH5 protein involved in meiotic chromosomal movements is a novel dynein activating adaptor
eLife 11:e78201.
https://doi.org/10.7554/eLife.78201

Share this article

https://doi.org/10.7554/eLife.78201

Categories and tags

Research organism

Further reading

    1. Cell Biology

    Stratification of enterochromaffin cells by single-cell expression analysis

    Yan Song, Linda J Fothergill ... Gene W Yeo
    Research Article

    Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify 14 EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic, and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.

    1. Cell Biology

    Small-molecule activation of TFEB alleviates Niemann–Pick disease type C via promoting lysosomal exocytosis and biogenesis

    Kaili Du, Hongyu Chen ... Dan Li
    Research Article

    Niemann–Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.

    1. Cell Biology
    2. Developmental Biology

    Lens Development: Bringing signaling complexity into focus

    Sarah Y Coomson, Salil A Lachke
    Insight

    A study in mice reveals key interactions between proteins involved in fibroblast growth factor signaling and how they contribute to distinct stages of eye lens development.