1. Cell Biology
  2. Developmental Biology

Negative feedback couples Hippo pathway activation with Kibra degradation independent of Yorkie-mediated transcription

  1. Sherzod A Tokamov
  2. Ting Su
  3. Anne Ullyot
  4. Richard G Fehon  Is a corresponding author
  1. University of Chicago, United States
  2. UT Southwestern Medical Center, United States
https://doi.org/10.7554/eLife.62326
Share this article
Cite this article
  1. Sherzod A Tokamov
  2. Ting Su
  3. Anne Ullyot
  4. Richard G Fehon
(2021)
Negative feedback couples Hippo pathway activation with Kibra degradation independent of Yorkie-mediated transcription
eLife 10:e62326.
https://doi.org/10.7554/eLife.62326
  2. Download BibTeX
  3. Download .RIS

Abstract

The Hippo pathway regulates tissue growth in many animals. Multiple upstream components promote Hippo pathway activity, but the organization of these different inputs, the degree of crosstalk between them, and whether they are regulated in a distinct manner is not well understood. Kibra activates the Hippo pathway by recruiting the core Hippo kinase cassette to the apical cortex. Here we show that the Hippo pathway downregulates Drosophila Kibra levels independently of Yorkie-mediated transcription. We find that Hippo signaling complex formation promotes Kibra degradation via SCFSlimb-mediated ubiquitination, that this effect requires Merlin, Salvador, Hippo, and Warts, and that this mechanism functions independently of other upstream Hippo pathway activators. Moreover, Kibra degradation appears patterned by differences in mechanical tension across the wing. We propose that Kibra degradation mediated by Hippo pathway components and regulated by cytoskeletal tension serves to control Kibra-driven Hippo pathway activation and ensure optimally scaled and patterned tissue growth.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Sherzod A Tokamov

    Committee on Development, Regeneration and Stem Cell Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Ting Su

    Department of Physiology, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1124-517X

  3. Anne Ullyot

    Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Richard G Fehon

    Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, United States
    For correspondence
    rfehon@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4889-2602

Funding

National Institute of Neurological Disorders and Stroke (NS034783)

  • Richard G Fehon

National Institute of General Medical Sciences (T32 GM007183)

  • Sherzod A Tokamov

National Science Foundation (Graduate Research Fellowship)

  • Sherzod A Tokamov

S. A. T. conceptualized the project, performed most of the experiments and data collection, and wrote the manuscript. R. G. F. conceptualized supervised all aspects of the project, and helped writing the manuscript. Both S. A. T. and R. G. F. agreed to submit the work for publication.

Copyright

© 2021, Tokamov 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

  • 2,059
    views
  • 6
    citations

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

Download links

Share this article

https://doi.org/10.7554/eLife.62326

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.