INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling

  1. Phi H Luong
  2. Matija Hedl
  3. Jie Yan
  4. Tao Zuo
  5. Tian-Min Fu
  6. Xiaomo Jiang
  7. Jay R Thiagarajah
  8. Steen H Hansen
  9. Cammie F Lesser
  10. Hao Wu
  11. Clara Abraham
  12. Wayne I Lencer  Is a corresponding author
  1. Harvard Medical School, United States
  2. Yale University, United States
  3. Novartis Institutes for Biomedical Research, United States
  4. Massachusetts General Hospital, United States

Abstract

Homeostasis at mucosal surfaces requires cross-talk between the environment and barrier epithelial cells. Disruption of barrier function typifies mucosal disease. Here we elucidate a bifunctional role in coordinating this cross-talk for the inflammatory bowel disease risk-gene INAVA. Both activities require INAVA's DUF3338 domain (renamed CUPID). CUPID stably binds the cytohesin ARF-GEF ARNO to effect lateral membrane F-actin assembly underlying cell-cell junctions and barrier function. Unexpectedly, when bound to CUPID, ARNO affects F-actin dynamics in the absence of its canonical activity as a guanine nucleotide-exchange factor. Upon exposure to IL-1β, INAVA relocates to form cytosolic puncta, where CUPID amplifies TRAF6-dependent polyubiquitination and inflammatory signaling. In this case, ARNO binding to CUPID negatively-regulates polyubiquitination and the inflammatory response. INAVA and ARNO act similarly in primary human macrophages responding to IL-1β and NOD2 agonists. Thus, INAVA-CUPID exhibits dual functions, coordinated directly by ARNO, that bridge epithelial barrier function with extracellular signals and inflammation.

Data availability

All data analysed during this study are included in the manuscript. Source data have been provided for Figure 3 C-F.

Article and author information

Author details

  1. Phi H Luong

    Department of Pediatrics, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  2. Matija Hedl

    Department of Medicine, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
  3. Jie Yan

    Department of Medicine, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
  4. Tao Zuo

    Department of Pediatrics, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  5. Tian-Min Fu

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  6. Xiaomo Jiang

    Novartis Institutes for Biomedical Research, Cambridge, United States
    Competing interests
    Xiaomo Jiang, is affiliated with Novartis. The author has no other competing interests to declare.
  7. Jay R Thiagarajah

    Department of Pediatrics, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  8. Steen H Hansen

    Department of Pediatrics, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  9. Cammie F Lesser

    Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Cambridge, United States
    Competing interests
    No competing interests declared.
  10. Hao Wu

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  11. Clara Abraham

    Department of Medicine, Yale University, New Haven, United States
    Competing interests
    No competing interests declared.
  12. Wayne I Lencer

    Department of Pediatrics, Harvard Medical School, Boston, United States
    For correspondence
    Wayne.Lencer@childrens.harvard.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7346-2730

Funding

National Institutes of Health (T32HD007466)

  • Phi H Luong

Crohn's and Colitis Foundation of America (Career Development Award)

  • Phi H Luong

Boston Children's Hospital (Rubin-Wolpow Fellowship)

  • Phi H Luong

National Institutes of Health (DK099097)

  • Clara Abraham

National Institutes of Health (DK048106)

  • Wayne I Lencer

National Institutes of Health (DK084424)

  • Wayne I Lencer

National Institutes of Health (P30 DK034854)

  • Wayne I Lencer

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

Reviewing Editor

  1. Kiyoshi Takeda, Osaka University, Japan

Publication history

  1. Received: May 21, 2018
  2. Accepted: October 15, 2018
  3. Accepted Manuscript published: October 25, 2018 (version 1)
  4. Version of Record published: November 9, 2018 (version 2)

Copyright

© 2018, Luong 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.

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  1. Phi H Luong
  2. Matija Hedl
  3. Jie Yan
  4. Tao Zuo
  5. Tian-Min Fu
  6. Xiaomo Jiang
  7. Jay R Thiagarajah
  8. Steen H Hansen
  9. Cammie F Lesser
  10. Hao Wu
  11. Clara Abraham
  12. Wayne I Lencer
(2018)
INAVA-ARNO complexes bridge mucosal barrier function with inflammatory signaling
eLife 7:e38539.
https://doi.org/10.7554/eLife.38539
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