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RUN and FYVE domain-containing protein 4 enhances autophagy and lysosome tethering in response to Interleukin-4

Seigo Terawaki1, Voahirana Camosseto1, Francesca Prete1

  • 1Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université UM2, Institut National de la Santé et de la Recherche Médicale U1104, Centre National de la Recherche Scientifique UMR7280, 13288 Marseille, France.

The Journal of Cell Biology
|September 30, 2015
PubMed

Insights

RUN and FYVE domain-containing protein 4 (RUFY4) enhances autophagy in dendritic cells (DCs) upon interleukin-4 (IL-4) exposure. This boosts antigen presentation and controls pathogen replication, identifying RUFY4 as a key regulator in immune cells.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Autophagy is a crucial cellular degradation process regulated by various external cues.
  • Specific molecular regulators of autophagy, especially those context-dependent, are not well-characterized.
  • Dendritic cells (DCs) play a vital role in immune responses, but their autophagic regulation is complex.

Purpose of the Study:

  • To investigate the role of RUN and FYVE domain-containing protein 4 (RUFY4) in regulating macroautophagy.
  • To elucidate the mechanism by which interleukin-4 (IL-4) influences autophagy in dendritic cells.
  • To determine the functional consequences of RUFY4-mediated autophagy in immune responses.

Main Methods:

  • Primary dendritic cells (DCs) were differentiated with or without IL-4 exposure.
  • Autophagy flux was assessed by monitoring LC3 degradation and autophagosome formation.
  • RUFY4 expression levels were quantified.
  • mTORC1 signaling pathway activity was analyzed.
  • Antigen presentation by MHC II molecules was evaluated.
  • Infection models using Brucella abortus were employed.

Main Results:

  • Interleukin-4 (IL-4) treatment during DC differentiation significantly enhanced autophagy flux.
  • IL-4 induced the expression of RUFY4, a positive regulator of macroautophagy.
  • RUFY4 promoted LC3 degradation, Syntaxin 17-positive autophagosome formation, and lysosome tethering.
  • Enhanced autophagy in IL-4-treated DCs and RUFY4-expressing cells improved endogenous antigen presentation via MHC II.
  • Increased autophagy facilitated host control of Brucella abortus replication.

Conclusions:

  • RUFY4 is identified as a novel molecular regulator that promotes macroautophagy in primary dendritic cells.
  • IL-4 signaling enhances autophagy in DCs, partly through the induction of RUFY4 and mTORC1 regulation.
  • RUFY4-mediated enhancement of autophagy influences endosome dynamics, antigen presentation, and host defense against intracellular pathogens.
  • RUFY4 represents a unique molecule linking immune cell-specific environmental cues to autophagic regulation and immune function.

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