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Reply to Lahiri et al.: APPealing for a role in cellular iron efflux

  • Daniel J. Kosman
    Correspondence
    To whom correspondence should be addressed: Dept. of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 955 Main St., Buffalo, NY 14203. Tel.: 716-829-2317
    Affiliations
    Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14203
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Open AccessPublished:June 14, 2019DOI:https://doi.org/10.1074/jbc.RL119.009249
      Lahiri et al. (
      • Lahiri D.K.
      • Maloney B.
      • Wang R.
      APPealing for a role in cellular iron efflux.
      ) expressed concern that by not detecting FRET between ferroportin-CFP and APP-YFP,
      The abbreviations used are: APP
      β-amyloid precursor protein
      sAPP
      secreted APP
      Fpn
      ferroportin
      YFP
      yellow fluorescent protein.
      2The abbreviations used are: APP
      β-amyloid precursor protein
      sAPP
      secreted APP
      Fpn
      ferroportin
      YFP
      yellow fluorescent protein.
      we “hinted that APP is unnecessary for ferroportin-supported Fe efflux.” There is no question that APP is unnecessary for ferroportin-dependent Fe efflux, as illustrated by the work by MacKenzie and co-workers (
      • Mitchell C.J.
      • Shawki A.
      • Ganz T.
      • Nemeth E.
      • Mackenzie B.
      Functional properties of human ferroportin, a cellular iron exporter reactive also with cobalt and zinc.
      ), who, using expression of Fpn in Xenopus oocytes, have provided details of ferroportin function. Also, we have shown that whereas knockdown of the essential ferroxidase hephaestin reduces iron efflux in primary hippocampal neurons, knockdown of APP does not (
      • Ji C.
      • Steimle B.L.
      • Bailey D.K.
      • Kosman D.J.
      The ferroxidase hephaestin but not amyloid precursor protein is required for ferroportin-supported iron efflux in primary hippocampal neurons.
      ). However, there is no question of a physiologic relationship between APP and cell iron metabolism, as Dr. Lahiri’s work has made abundantly clear. The specific conclusion of Dlouhy et al. (
      • Dlouhy A.C.
      • Bailey D.K.
      • Steimle B.L.
      • Parker H.V.
      • Kosman D.J.
      Fluorescence resonance energy transfer links membrane ferroportin, hephaestin but not ferroportin, amyloid precursor protein complex with iron efflux.
      ) was that the form of APP that enhances the membrane presentation of Fpn and thus Fe efflux is sAPP, not the endogenous, unprocessed form. sAPP has this property, as do helices from the protein’s E2 domain or a synthetic peptide from that domain, all three of which contain the REWEE motif that Bush and co-workers (
      • Duce J.A.
      • Tsatsanis A.
      • Cater M.A.
      • James S.A.
      • Robb E.
      • Wikhe K.
      • Leong S.L.
      • Perez K.
      • Johanssen T.
      • Greenough M.A.
      • Cho H.-H.
      • Galatis D.
      • Moir R.D.
      • Masters C.L.
      • McLean C.
      • et al.
      Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease.
      ) first identified as being linked to a role for APP in Fpn-mediated iron efflux. Our genetically encoded fluorescent proteins were used solely to determine whether native, membrane-associated APP and Fpn formed a complex; they do not, a finding in support of our conclusion that only soluble APP species bind to Fpn. In this context, concerns about secretase processing are moot. Note that the self-association of APP has been demonstrated using our FRET approach (
      • Kaden D.
      • Voigt P.
      • Munter L.M.
      • Bobowski K.D.
      • Schaefer M.
      • Multhaup G.
      Subcellular localization and dimerization of APLP1 are strikingly different from APP and APLP2.
      ), as have APP, BACE1 trafficking, and Aβ production (
      • Kinoshita A.
      • Fukumoto H.
      • Shah T.
      • Whelan C.M.
      • Irizarry M.C.
      • Hyman B.T.
      Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes.
      ). In summary, we hope our work will encourage researchers to appreciate the strong likelihood that among the physiologic functions performed by APP family members is one related to cell iron metabolism; in the closed compartment that is the brain, this role may be paramount and thus critical to understanding the link between Alzheimer’s disease and iron. Importantly, in this closed compartment, sAPP released from any of the cell types in the neurovascular unit will modulate Fpn activity. We miss this juxtacrine relationship by focusing on APP itself.

      References

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        • Maloney B.
        • Wang R.
        APPealing for a role in cellular iron efflux.
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        Am. J. Physiol. Cell Physiol. 2014; 306 (24304836): C450-C459
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        • Steimle B.L.
        • Bailey D.K.
        • Kosman D.J.
        The ferroxidase hephaestin but not amyloid precursor protein is required for ferroportin-supported iron efflux in primary hippocampal neurons.
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      Linked Article

      • APPealing for a role in cellular iron efflux
        Journal of Biological ChemistryVol. 294Issue 24
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          Dlouhy et al. (1) recently refined how β-amyloid precursor protein (APP)2 participates in iron (Fe) efflux and hinted that APP may be unnecessary for ferroportin-supported Fe efflux. APP and Fe efflux have long been our interest, given recent work on the APP mRNA 5′-UTR and how regulation of APP translation operates through an interleukin-1 acute box, an iron response element (IRE), where iron-responsive protein 1 (IRP1) binds, and a target sequence for microRNA-346 (2). Untangling the roles of IRE, IRP1, interleukin-1, and miR-346 at the APP 5′-UTR is critical in Alzheimer’s disease (AD).
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