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Potential dual function of PQ-loop proteins such as cystinosin

  • Vladimir Saudek
    Correspondence
    To whom correspondence should be addressed.
    Affiliations
    From the Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge Metabolic Research Laboratories, CB2 OQQ Cambridge, United Kingdom
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Open AccessPublished:September 08, 2017DOI:https://doi.org/10.1074/jbc.L117.795278
      Zhang et al. (
      • Zhang J.
      • Johnson J.L.
      • He J.
      • Napolitano G.
      • Ramadass M.
      • Rocca C.
      • Kiosses W.B.
      • Bucci C.
      • Xin Q.
      • Gavathiotis E.
      • Cuervo A.M.
      • Cherqui S.
      • Catz S.D.
      Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate intracellular trafficking of the chaperone-mediated autophagy receptor LAMP2A.
      ) demonstrate convincingly that cystinosin has a dual function. In addition to its low-molecular-weight solute transport, it participates in small GTPase-regulated vesicle trafficking and lysosomal localization of LAMP2A, a protein regulating chaperone-mediated autophagy. If cystinosin is absent or impaired, LAMP2A is mislocalized. Such a protein-trafficking function has been suggested previously, based on a bioinformatics analysis (
      • Saudek V.
      Cystinosin, MPDU1, SWEETs, and KDELR belong to a well-defined protein family with putative function of cargo receptors involved in vesicle trafficking.
      ). Cystinosin belongs to a diverse family of homologous proteins named PQ-loop (
      • Saudek V.
      Cystinosin, MPDU1, SWEETs, and KDELR belong to a well-defined protein family with putative function of cargo receptors involved in vesicle trafficking.
      ). Some of the members have been shown to be solute transporters, e.g. plant SWEETs (
      • Chen L.Q.
      • Hou B.H.
      • Lalonde S.
      • Takanaga H.
      • Hartung M.L.
      • Qu X.Q.
      • Guo W.J.
      • Kim J.G.
      • Underwood W.
      • Chaudhuri B.
      • Chermak D.
      • Antony G.
      • White F.F.
      • Somerville S.C.
      • Mudgett M.B.
      • Frommer W.B.
      Sugar transporters for intercellular exchange and nutrition of pathogens.
      ); others have been shown to be protein cargo receptors in vesicle trafficking, e.g. KDEL receptors (
      • Capitani M.
      • Sallese M.
      The KDEL receptor: New functions for an old protein.
      ). The molecular functions of many of them, e.g. MPDU1 and CLPT1L, have not yet been found despite their involvement in important biological processes. The cargo-trafficking function has been described for mammalian SWEET1, alias RAG1AP1 (
      • Stokes A.J.
      • Wakano C.
      • Del Carmen K.A.
      • Koblan-Huberson M.
      • Turner H.
      Formation of a physiological complex between TRPV2 and RGA protein promotes cell surface expression of TRPV2.
      ), although not noticed when its solute transport was later discovered (
      • Chen L.Q.
      • Hou B.H.
      • Lalonde S.
      • Takanaga H.
      • Hartung M.L.
      • Qu X.Q.
      • Guo W.J.
      • Kim J.G.
      • Underwood W.
      • Chaudhuri B.
      • Chermak D.
      • Antony G.
      • White F.F.
      • Somerville S.C.
      • Mudgett M.B.
      • Frommer W.B.
      Sugar transporters for intercellular exchange and nutrition of pathogens.
      ). The most recent discovery of this dual function in cystinosin (
      • Zhang J.
      • Johnson J.L.
      • He J.
      • Napolitano G.
      • Ramadass M.
      • Rocca C.
      • Kiosses W.B.
      • Bucci C.
      • Xin Q.
      • Gavathiotis E.
      • Cuervo A.M.
      • Cherqui S.
      • Catz S.D.
      Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate intracellular trafficking of the chaperone-mediated autophagy receptor LAMP2A.
      ) suggests that it could be a general property of many other family members and should always be considered when investigating these important proteins. It could turn out to be particularly relevant for KDEL receptors that show several activities independent of their receptor function (
      • Capitani M.
      • Sallese M.
      The KDEL receptor: New functions for an old protein.
      ).

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