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

Terawaki, Seigo; Camosseto, Voahirana; Prete, Francesca; Wenger, Till; Papadopoulos, Alexia; Rondeau, Christiane; Combes, Alexis J.; Rodrígues, Christian Rodríguez; Manh, Thien‐Phong Vu; Fallet, Mathieu; English, Luc; Santamaría, Rodrigo; Soares, Ana Raquel; Weil, Tobias; Hammad, Hamida; Desjardins, Michel; Gorvel, Jean‐Pierre; Santos, Manuel A. S.; Gatti, Evelina; Pierre, Philippe

doi:10.1083/jcb.201501059

Cited by 59 publications

(77 citation statements)

References 54 publications

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“…Most of the identified genes have not been previously suggested to alter pathogen defense or autophagy; however, some genes that scored in these screens were supported by published findings. RUFY4 (RUN and FYVE domain containing 4) has recently been shown to positively regulate autophagy in response to the cytokine IL-4 (Terawaki et al, 2015). SCAMP3 (secretory carrier membrane protein 3), a gene that scored only in the intracellular bacterial replication screen, has been shown to affect intracellular localization of S. Typhimurium, a phenotype that can have consequences for bacterial replication in host cells (Mota et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk

et al. 2016

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SUMMARY Although numerous polymorphisms have been associated with inflammatory bowel disease (IBD), identifying the function of these genetic factors has proved challenging. Here we identified a role for nine genes in IBD susceptibility loci in antibacterial autophagy and characterized a role for one of these genes, GPR65, in maintaining lysosome function. Mice lacking Gpr65, a proton-sensing G protein-coupled receptor, showed increased susceptibly to bacteria-induced colitis. Epithelial cells and macrophages lacking GPR65 exhibited impaired clearance of intracellular bacteria and accumulation of aberrant lysosomes. Similarly, IBD patient cells and epithelial cells expressing an IBD-associated missense variant, GPR65 I231L, displayed aberrant lysosomal pH resulting in lysosomal dysfunction, impaired bacterial restriction, and altered lipid droplet formation. The GPR65 I231L polymorphism was sufficient to confer decreased GPR65 signaling. Collectively, these data establish a role for GPR65 in IBD susceptibility and identify lysosomal dysfunction as a potentially causative element in IBD pathogenesis with effects on cellular homeostasis and defense.

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Section: Resultsmentioning

confidence: 99%

Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk

et al. 2016

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“…Therefore, in vitro, in the course of DC HIV infection, the cytokine environment might not significantly influence the cellular localization of HIV Gag and Env. Interestingly, in this regard note that IL-4, used to generate DC in our study, enhances the autophagic flux and also favors endogenous MHC-IIrestricted bacterial Ag presentation (86).…”

Section: Discussionmentioning

confidence: 99%

HIV-Infected Dendritic Cells Present Endogenous MHC Class II–Restricted Antigens to HIV-Specific CD4+ T Cells

Coulon

Richetta

Rouers

et al. 2016

The Journal of Immunology

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It is widely assumed that CD4+ T cells recognize antigenic peptides (epitopes) derived solely from incoming, exogenous, viral particles or proteins. However, alternative sources of MHC class II (MHC-II)–restricted Ags have been described, in particular epitopes derived from newly synthesized proteins (so-called endogenous). In this study, we show that HIV-infected dendritic cells (DC) present MHC-II–restricted endogenous viral Ags to HIV-specific (HS) CD4+ T cells. This endogenous pathway functions independently of the exogenous route for HIV Ag presentation and offers a distinct possibility for the immune system to activate HS CD4+ T cells. We examined the implication of autophagy, which plays a crucial role in endogenous viral Ag presentation and thymic selection of CD4+ T cells, in HIV endogenous presentation. We show that infected DC do not use autophagy to process MHC-II–restricted HIV Ags. This is unlikely to correspond to a viral escape from autophagic degradation, as infecting DC with Nef- or Env-deficient HIV strains did not impact HS T cell activation. However, we demonstrate that, in DC, specific targeting of HIV Ags to autophagosomes using a microtubule-associated protein L chain 3 (LC3) fusion protein effectively enhances and broadens HS CD4+ T cell responses, thus favoring an endogenous MHC-II–restricted presentation. In summary, in DC, multiple endogenous presentation pathways lead to the activation of HS CD4+ T cell responses. These findings will help in designing novel strategies to activate HS CD4+ T cells that are required for CTL activation/maintenance and B cell maturation.

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“…Ap3b1 ‐KO ( B6Pin.C3‐Ap3b1 pe / J ), IFNb E YFP ( B6.129‐Ifnb1 tm1Lky ) reporter mice and Itgal ‐KO ( B6.129S7‐Itgal tm1Bll ) mice were purchased from Jackson Laboratories, USA. Ifnar1 ‐KO (B6.129S2‐Ifnar1 tm1agt ) , Myd88 ‐KO ( B6.129P2‐Myd88 tm1Aki ) , Tlr9 ‐KO (129P2‐Tlr9 tm1Aki ), Tlr7 ‐KO ( B6.129P2‐Tlr7 tm1Aki ), Irf7 ‐KO ( B6.129P2‐Irf7 tm1Ttg ) (Honda et al , ), Ikka A/A ( B6.129P2‐Chuk tm2Mka ) (Cao et al , ), Ikbkb ΔItgax (Baratin et al , ), and Atg5 fl/fl ( B6.129S‐Atg5 tm1Myok ) (Hara et al , ; Terawaki et al , ) mice were backcrossed on C57BL/6 background for over eight generations. Rosa26 ‐LoxP_STOP_LoxP(LSL)‐Red Fluorescent protein, Rosa26 ‐LSL‐RFP ( B6‐Gt(ROSA)26Sor tm1Hjf ) mice (Luche et al , ) were kindly provided by B. Malissen (CIML).…”

Section: Methodsmentioning

confidence: 99%

Molecular dissection of plasmacytoid dendritic cell activation in vivo during a viral infection

et al. 2018

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Plasmacytoid dendritic cells (pDC) are the major source of type I interferons (IFN‐I) during viral infections, in response to triggering of endosomal Toll‐like receptors (TLRs) 7 or 9 by viral single‐stranded RNA or unmethylated CpG DNA, respectively. Synthetic ligands have been used to disentangle the underlying signaling pathways. The adaptor protein AP3 is necessary to transport molecular complexes of TLRs, synthetic CpG DNA, and MyD88 into endosomal compartments allowing interferon regulatory factor 7 (IRF7) recruitment whose phosphorylation then initiates IFN‐I production. High basal expression of IRF7 by pDC and its further enhancement by positive IFN‐I feedback signaling appear to be necessary for robust cytokine production. In contrast, we show here that in vivo during mouse cytomegalovirus (MCMV) infection pDC produce high amounts of IFN‐I downstream of the TLR9‐to‐MyD88‐to‐IRF7 signaling pathway without requiring IFN‐I positive feedback, high IRF7 expression, or AP3‐driven endosomal routing of TLRs. Hence, the current model of the molecular requirements for professional IFN‐I production by pDC, established by using synthetic TLR ligands, does not strictly apply to a physiological viral infection.

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

Abstract: Interleukin-4 boosts the capacity of dendritic cells to present endogenous antigens on MHC II and to resist bacterial infection through a mechanism shown to be partially dependent on RUFY4 expression.

Cited by 59 publications

References 54 publications

Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk

Genetic Coding Variant in GPR65 Alters Lysosomal pH and Links Lysosomal Dysfunction with Colitis Risk

HIV-Infected Dendritic Cells Present Endogenous MHC Class II–Restricted Antigens to HIV-Specific CD4+ T Cells

Molecular dissection of plasmacytoid dendritic cell activation in vivo during a viral infection

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