title: The intracellular domain of cell adhesion molecule 1 is present in emphysematous lungs and induces lung epithelial cell apoptosis.
abstract: BACKGROUND
  Pulmonary emphysema is characterized histologically by destruction of alveolar walls and enlargement of air spaces due to lung epithelial cell apoptosis. Cell adhesion molecule 1 (CADM1) is an immunoglobulin superfamily member expressed in lung epithelial cells. CADM1 generates a membrane-associated C-terminal fragment, αCTF, through A disintegrin- and metalloprotease-10-mediated ectodomain shedding, subsequently releasing the intracellular domain (ICD) through γ-secretase-mediated intramembrane shedding of αCTF. αCTF localizes to mitochondria and induces apoptosis in lung epithelial cells. αCTF contributes to the development and progression of emphysema as a consequence of increased CADM1 ectodomain shedding. The purpose of this study was to examine whether the ICD makes a similar contribution.
  
  
  RESULTS
  The ICD was synthesized as a 51-amino acid peptide, and its mutant was synthesized by substituting seven amino acids and deleting two amino acids. These peptides were labeled with fluorescein isothiocyanate and were introduced into various cell lines. ICD peptide-derived fluorescence was well visualized in lung epithelial cells at the site of Mitotracker mitochondrial labeling, but was detected in locations other than mitochondria in other cell types. Mutant peptide-derived fluorescence was detected in locations other than mitochondria, even in lung epithelial cells. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays revealed that transduction of the ICD peptide increased the proportion of apoptotic cells 2- to 5-fold in the lung epithelial cell lines, whereas the mutant peptide did not. Abundance of the ICD was below the Western blot detection limit in emphysematous (n = 4) and control (n = 4) human lungs. However, the ICD was detected only in emphysematous lungs when it was immunoprecipitated with anti-CADM1 antibody (4/4 vs. 0/4, P = 0.029).
  
  
  CONCLUSIONS
  As the abundance of ICD molecules was sparse but present, increased CADM1 shedding appeared to contribute to the development of emphysema by generating αCTF and the ICD in lung epithelial cells.
authors.affiliation: Department of Pathology, Faculty of Medicine, Kinki University, Osaka, 589-8511, Japan. hagiyama@med.kindai.ac.jp.
authors.forename: Man
authors.initials: M
authors.lastname: Hagiyama
authors.affiliation: Department of Pathology, Faculty of Medicine, Kinki University, Osaka, 589-8511, Japan. azusa618@med.kindai.ac.jp.
authors.forename: Azusa
authors.initials: A
authors.lastname: Yoneshige
authors.affiliation: Department of Pathology, Faculty of Medicine, Kinki University, Osaka, 589-8511, Japan. takao@med.kindai.ac.jp.
authors.forename: Takao
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Pathology, Faculty of Medicine, Kinki University, Osaka, 589-8511, Japan. yasusato@med.kindai.ac.jp.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. tmimae.0907.surgery@gmail.com.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mimae
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. morihito@hiroshima-u.ac.jp.
authors.forename: Morihito
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Pathology, Faculty of Medicine, Kinki University, Osaka, 589-8511, Japan. aito@med.kindai.ac.jp.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ito
mesh_terms: D000818:Animals; D017209:Apoptosis; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D011656:Pulmonary Emphysema / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology
chemical_list: C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins