Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in C. elegans

  1. Yanan Sun
  2. Meijiao Li
  3. Dongfeng Zhao
  4. Xin Li
  5. Chonglin Yang
  6. Xiaochen Wang  Is a corresponding author
  1. Institute of Biophysics Chinese Academy of Sciences, China
  2. Yunnan University, China

Abstract

Lysosomes play important roles in cellular degradation to maintain cell homeostasis. In order to understand whether and how lysosomes alter with age and contribute to lifespan regulation, we characterized multiple properties of lysosomes during the aging process in C. elegans. We uncovered age-dependent alterations in lysosomal morphology, motility, acidity and degradation activity, all of which indicate a decline in lysosome function with age. The age-associated lysosomal changes are suppressed in the long-lived mutants daf-2, eat-2 and isp-1, which extend lifespan by inhibiting insulin/IGF-1 signaling, reducing food intake and impairing mitochondrial function, respectively. We found that 43 lysosome genes exhibit reduced expression with age, including genes encoding subunits of the proton pump V-ATPase and cathepsin proteases. The expression of lysosome genes is upregulated in the long-lived mutants, and this upregulation requires the functions of DAF-16/FOXO and SKN-1/NRF2 transcription factors. Impairing lysosome function affects clearance of aggregate-prone proteins and disrupts lifespan extension in daf-2, eat-2 and isp-1 worms. Our data indicate that lysosome function is modulated by multiple longevity pathways and is important for lifespan extension.

Data availability

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

Article and author information

Author details

  1. Yanan Sun

    National Laboratory of Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, China
    Competing interests
    No competing interests declared.
  2. Meijiao Li

    School of Life Sciences, Yunnan University, Kunming, China
    Competing interests
    No competing interests declared.
  3. Dongfeng Zhao

    National Laboratory of Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, China
    Competing interests
    No competing interests declared.
  4. Xin Li

    National Laboratory of Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, China
    Competing interests
    No competing interests declared.
  5. Chonglin Yang

    School of Life Sciences, Yunnan University, Kunming, China
    Competing interests
    No competing interests declared.
  6. Xiaochen Wang

    National Laboratory of Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, China
    For correspondence
    wangxiaochen@ibp.ac.cn
    Competing interests
    Xiaochen Wang, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4344-0925

Funding

Ministry of Science and Technology of the People's Republic of China (2016YFA0500203)

  • Xiaochen Wang

National Natural Science Foundation of China (3163001,91754203)

  • Xiaochen Wang

The Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000)

  • Xiaochen Wang

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

Reviewing Editor

  1. Mahak Sharma, Indian Institute of Science Education and Research Mohali, India

Publication history

  1. Received: February 4, 2020
  2. Accepted: May 25, 2020
  3. Accepted Manuscript published: June 2, 2020 (version 1)
  4. Version of Record published: June 5, 2020 (version 2)

Copyright

© 2020, Sun 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

  • 7,730
    Page views
  • 1,141
    Downloads
  • 40
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

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. Yanan Sun
  2. Meijiao Li
  3. Dongfeng Zhao
  4. Xin Li
  5. Chonglin Yang
  6. Xiaochen Wang
(2020)
Lysosome activity is modulated by multiple longevity pathways and is important for lifespan extension in C. elegans
eLife 9:e55745.
https://doi.org/10.7554/eLife.55745
  1. Further reading

Further reading

    1. Cell Biology
    Benjamin Barsi-Rhyne, Aashish Manglik, Mark von Zastrow
    Research Article Updated

    β-Arrestins are master regulators of cellular signaling that operate by desensitizing ligand-activated G-protein-coupled receptors (GPCRs) at the plasma membrane and promoting their subsequent endocytosis. The endocytic activity of β-arrestins is ligand dependent, triggered by GPCR binding, and increasingly recognized to have a multitude of downstream signaling and trafficking consequences that are specifically programmed by the bound GPCR. However, only one biochemical ‘mode’ for GPCR-mediated triggering of the endocytic activity is presently known – displacement of the β-arrestin C-terminus (CT) to expose clathrin-coated pit-binding determinants that are masked in the inactive state. Here, we revise this view by uncovering a second mode of GPCR-triggered endocytic activity that is independent of the β-arrestin CT and, instead, requires the cytosolic base of the β-arrestin C-lobe (CLB). We further show each of the discrete endocytic modes is triggered in a receptor-specific manner, with GPCRs that bind β-arrestin transiently (‘class A’) primarily triggering the CLB-dependent mode and GPCRs that bind more stably (‘class B’) triggering both the CT and CLB-dependent modes in combination. Moreover, we show that different modes have opposing effects on the net signaling output of receptors – with the CLB-dependent mode promoting rapid signal desensitization and the CT-dependent mode enabling prolonged signaling. Together, these results fundamentally revise understanding of how β-arrestins operate as efficient endocytic adaptors while facilitating diversity and flexibility in the control of cell signaling.

    1. Cell Biology
    2. Structural Biology and Molecular Biophysics
    Jie Li, Jiayi Wu ... Eunhee Choi
    Research Article

    The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked homodimers in the apo-state; however, their ligand binding properties and the structures in the active state differ substantially. It has been proposed that the disulfide-linked C-terminal segment of α-chain (αCTs) of the IR and IGF1R control the cooperativity of ligand binding and regulate the receptor activation. Nevertheless, the molecular basis for the roles of disulfide-linked αCTs in IR and IGF1R activation are still unclear. Here, we report the cryo-EM structures of full-length mouse IGF1R/IGF1 and IR/insulin complexes with modified αCTs that have increased flexibility. Unlike the Γ-shaped asymmetric IGF1R dimer with a single IGF1 bound, the IGF1R with the enhanced flexibility of αCTs can form a T-shaped symmetric dimer with two IGF1s bound. Meanwhile, the IR with non-covalently linked αCTs predominantly adopts an asymmetric conformation with four insulins bound, which is distinct from the T-shaped symmetric IR. Using cell-based experiments, we further showed that both IGF1R and IR with the modified αCTs cannot activate the downstream signaling potently. Collectively, our studies demonstrate that the certain structural rigidity of disulfide-linked αCTs is critical for optimal IR and IGF1R signaling activation.