title: Interactions between FATP4 and ichthyin in epidermal lipid processing may provide clues to the pathogenesis of autosomal recessive congenital ichthyosis.
abstract: BACKGROUND
  Autosomal recessive congenital ichthyosis (ARCI) is caused by mutations in ≥10 different genes, of which transglutaminase-1 (TGM1) predominates. A rare form is ichthyosis prematurity syndrome (IPS) caused by mutations in SLC27A4 encoding fatty acid transporter protein 4 (FATP4), believed to be an acyl-CoA synthetase activating long- and very-long-chain FA. Another ARCI is caused by mutations in NIPAL4, coding for ichthyin, which is proposed to be a magnesium transporter or a trans-membrane receptor. A possible interaction between FATP4 and ichthyin has not been studied before.
  
  
  OBJECTIVE
  To find common denominators in the pathogenesis of ARCI.
  
  
  METHODS
  FATP4 and ichthyin were analyzed by immunofluorescence and proximity ligation assay (PLA) in healthy and ARCI patient skin and in in vitro models of ARCI epidermis.
  
  
  RESULTS
  Both proteins were expressed in the upper stratum granulosum of normal epidermis and PLA confirmed a close interaction between FATP4 and ichthyin. In IPS skin lacking FATP4 we found reduced ichthyin expression and this finding could be reproduced in organotypic epidermis with siRNA silenced SLC27A4. In contrast, increased FATP4 staining was found in patients with ichthyin (NIPAL4) mutations and in organotypic epidermis with silenced NIPAL4. In patients with TGM1 mutations, the expression of both FATP4 and ichthyin was increased, but the PLA signal was low probably indicating a malfunctioning protein interaction.
  
  
  CONCLUSIONS
  Our study suggests that FATP4, ichthyin and TGM1 interact in lipid processing essential for maintaining the epidermal barrier function. It is also hypothesized that ichthyin serves as Mg(2+)-transporter for FATP4 in this process.
authors.affiliation: Department of Medical Sciences, Dermatology and Venereology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.forename: Anders
authors.initials: A
authors.lastname: Vahlquist
authors.forename: Hans
authors.initials: H
authors.lastname: Törmä
mesh_terms: D000328:Adult; D015783:Aniridia; D001692:Biological Transport; D004817:Epidermis / Q000378:metabolism; D050612:Fatty Acid Transport Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007057:Ichthyosis / Q000235:genetics* / Q000503:physiopathology*; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases / Q000235:genetics* / Q000503:physiopathology*; D015603:Keratinocytes / Q000378:metabolism; D007668:Kidney / Q000002:abnormalities; D050356:Lipid Metabolism; D008274:Magnesium / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011596:Psychomotor Disorders; D034741:RNA, Small Interfering / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D050612:Fatty Acid Transport Proteins; C499859:NIPAL4 protein, human; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C493571:SLC27A4 protein, human; D011503:Transglutaminases; C105804:transglutaminase 1; D008274:Magnesium