title: A proteolytic modification of AIM promotes its renal excretion.
abstract: Apoptosis inhibitor of macrophage (AIM, encoded by cd5l) is a multi-functional circulating protein that has a beneficial role in the regulation of a broad range of diseases, some of which are ameliorated by AIM administration in mice. In blood, AIM is stabilized by association with IgM pentamers and maintains its high circulating levels. The mechanism regulating the excessive accumulation of blood AIM remains unknown, although it is important, since a constitutive increase in AIM levels promotes chronic inflammation. Here we found a physiological AIM-cleavage process that induces destabilization of AIM and its excretion in urine. In blood, IgM-free AIM appeared to be cleaved and reduced in size approximately 10 kDa. Cleaved AIM was unable to bind to IgM and was selectively filtered by the glomerulus, thereby excreted in urine. Amino acid substitution at the cleavage site resulted in no renal excretion of AIM. Interestingly, cleaved AIM retained a comparable potency with full-length AIM in facilitating the clearance of dead cell debris in injured kidney, which is a key response in the recovery of acute kidney injury. Identification of AIM-cleavage and resulting functional modification could be the basis for designing safe and efficient AIM therapy for various diseases.
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Sugisawa
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Emiri
authors.initials: E
authors.lastname: Hiramoto
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takai
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Senda
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nakashima
authors.affiliation: Division of Human Biology and Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Division of Human Biology and Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Lucas
authors.affiliation: Division of Human Biology and Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Morgan
authors.affiliation: Center for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Li
authors.affiliation: Center for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Yamamura
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Arai
authors.affiliation: Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.|AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 113-0033, Japan.|Max Planck-The University of Tokyo Center for Integrative Inflammology, Tokyo 113-0033, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Miyazaki
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D059748:Proteolysis; D051381:Rats; D051116:Receptors, Scavenger / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C492821:CD5L protein, human; D051116:Receptors, Scavenger