USP5/Leon deubiquitinase confines postsynaptic growth by maintaining ubiquitin homeostasis through Ubiquilin

  1. Chien-Hsiang Wang
  2. Yi-Chun Huang
  3. Pei-Yi Chen
  4. Ying-Ju Cheng
  5. Hsiu-Hua Kao
  6. Haiwei Pi
  7. Cheng-Ting Chien  Is a corresponding author
  1. Academia Sinica, Taiwan, Republic of China
  2. Chang Gung University, Taiwan, Republic of China

Abstract

Synapse formation and growth are tightly controlled processes. How synaptic growth is terminated after reaching proper size remains unclear. Here, we show that Leon, the Drosophila USP5 deubiquitinase, controls postsynaptic growth. In leon mutants, postsynaptic specializations of neuromuscular junctions are dramatically expanded, including the subsynaptic reticulum, the postsynaptic density, and the glutamate receptor cluster. Expansion of these postsynaptic features is caused by a disruption of ubiquitin homeostasis with accumulation of free ubiquitin chains and ubiquitinated substrates in the leon mutant. Accumulation of Ubiquilin (Ubqn), the ubiquitin receptor whose human homolog ubiquilin 2 is associated with familial amyotrophic lateral sclerosis, also contributes to defects in postsynaptic growth and ubiquitin homeostasis. Importantly, accumulations of postsynaptic proteins cause different aspects of postsynaptic overgrowth in leon mutants. Thus, the deubiquitinase Leon maintains ubiquitin homeostasis and proper Ubqn levels, preventing postsynaptic proteins from accumulation to confine postsynaptic growth.

Article and author information

Author details

  1. Chien-Hsiang Wang

    Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
  2. Yi-Chun Huang

    Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
  3. Pei-Yi Chen

    Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
  4. Ying-Ju Cheng

    Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
  5. Hsiu-Hua Kao

    Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
  6. Haiwei Pi

    Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan, Republic of China
    Competing interests
    The authors declare that no competing interests exist.
  7. Cheng-Ting Chien

    Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Republic of China
    For correspondence
    ctchien@gate.sinica.edu.tw
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7906-7173

Funding

Academia Sinica

  • Chien-Hsiang Wang
  • Yi-Chun Huang
  • Pei-Yi Chen
  • Ying-Ju Cheng
  • Cheng-Ting Chien

Ministry of Science and Technology, Taiwan

  • Chien-Hsiang Wang
  • Yi-Chun Huang
  • Pei-Yi Chen
  • Ying-Ju Cheng
  • Cheng-Ting Chien

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

Reviewing Editor

  1. Hugo J Bellen, Baylor College of Medicine, United States

Version history

  1. Received: March 16, 2017
  2. Accepted: May 9, 2017
  3. Accepted Manuscript published: May 10, 2017 (version 1)
  4. Version of Record published: May 19, 2017 (version 2)

Copyright

© 2017, Wang 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

  • 1,337
    Page views
  • 300
    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. Chien-Hsiang Wang
  2. Yi-Chun Huang
  3. Pei-Yi Chen
  4. Ying-Ju Cheng
  5. Hsiu-Hua Kao
  6. Haiwei Pi
  7. Cheng-Ting Chien
(2017)
USP5/Leon deubiquitinase confines postsynaptic growth by maintaining ubiquitin homeostasis through Ubiquilin
eLife 6:e26886.
https://doi.org/10.7554/eLife.26886

Share this article

https://doi.org/10.7554/eLife.26886

Further reading

    1. Developmental Biology
    2. Neuroscience
    Tariq Zaman, Daniel Vogt ... Michael R Williams
    Research Article

    The cell-type-specific expression of ligand/receptor and cell-adhesion molecules is a fundamental mechanism through which neurons regulate connectivity. Here, we determine a functional relevance of the long-established mutually exclusive expression of the receptor tyrosine kinase Kit and the trans-membrane protein Kit Ligand by discrete populations of neurons in the mammalian brain. Kit is enriched in molecular layer interneurons (MLIs) of the cerebellar cortex (i.e., stellate and basket cells), while cerebellar Kit Ligand is selectively expressed by a target of their inhibition, Purkinje cells (PCs). By in vivo genetic manipulation spanning embryonic development through adulthood, we demonstrate that PC Kit Ligand and MLI Kit are required for, and capable of driving changes in, the inhibition of PCs. Collectively, these works in mice demonstrate that the Kit Ligand/Kit receptor dyad sustains mammalian central synapse function and suggest a rationale for the affiliation of Kit mutation with neurodevelopmental disorders.

    1. Developmental Biology
    2. Neuroscience
    Smrithi Prem, Bharati Dev ... Emanuel DiCicco-Bloom
    Research Article

    Autism spectrum disorder (ASD) is defined by common behavioral characteristics, raising the possibility of shared pathogenic mechanisms. Yet, vast clinical and etiological heterogeneity suggests personalized phenotypes. Surprisingly, our iPSC studies find that six individuals from two distinct ASD-subtypes, idiopathic and 16p11.2 deletion, have common reductions in neural precursor cell (NPC) neurite outgrowth and migration even though whole genome sequencing demonstrates no genetic overlap between the datasets. To identify signaling differences that may contribute to these developmental defects, an unbiased phospho-(p)-proteome screen was performed. Surprisingly despite the genetic heterogeneity, hundreds of shared p-peptides were identified between autism subtypes including the mTOR pathway. mTOR signaling alterations were confirmed in all NPCs across both ASD-subtypes, and mTOR modulation rescued ASD phenotypes and reproduced autism NPC associated phenotypes in control NPCs. Thus, our studies demonstrate that genetically distinct ASD subtypes have common defects in neurite outgrowth and migration which are driven by the shared pathogenic mechanism of mTOR signaling dysregulation.