title: RNautophagy/DNautophagy possesses selectivity for RNA/DNA substrates.
abstract: Lysosomes can degrade various biological macromolecules, including nucleic acids, proteins and lipids. Recently, we identified novel nucleic acid-degradation systems termed RNautophagy/DNautophagy (abbreviated as RDA), in which RNA and DNA are directly taken up by lysosomes in an ATP-dependent manner and degraded. We also found that a lysosomal membrane protein, LAMP2C, the cytoplasmic region of which binds to RNA and DNA, functions, at least in part, as an RNA/DNA receptor in the process of RDA. However, it has been unclear whether RDA possesses selectivity for RNA/DNA substrates and the RNA/DNA sequences that are recognized by LAMP2C have not been determined. In the present study, we found that the cytosolic region of LAMP2C binds to poly-G/dG, but not to poly-A/dA, poly-C/dC, poly-dT or poly-U. Consistent with this binding activity, poly-G/dG was transported into isolated lysosomes via RDA, while poly-A/dA, poly-C/dC, poly-dT and poly-U were not. GGGGGG or d(GGGG) sequences are essential for the interaction between poly-G/dG and LAMP2C. In addition to poly-G/dG, G/dG-rich sequences, such as a repeated GGGGCC sequence, interacted with the cytosolic region of LAMP2C. Our findings indicate that RDA does possess selectivity for RNA/DNA substrates and that at least some consecutive G/dG sequence(s) can mediate RDA.
authors.affiliation: Department of Degenerative Neurological Disease, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Hase
authors.affiliation: Department of Degenerative Neurological Disease, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan Department of Electrical Engineering and Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Sinjuku-ku, Tokyo 162-8480, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Degenerative Neurological Disease, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Hisae
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: Department of Degenerative Neurological Disease, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Aizawa
authors.affiliation: Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hakuno
authors.affiliation: Department of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Degenerative Neurological Disease, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.affiliation: Department of Degenerative Neurological Disease, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan kabuta@ncnp.go.jp.
authors.forename: Tomohiro
authors.identifier: http://orcid.org/0000-0002-3058-2596
authors.initials: T
authors.lastname: Kabuta
mesh_terms: D000818:Animals; D001343:Autophagy; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D019175:DNA Methylation; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D011068:Poly G / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000378:metabolism*
chemical_list: D052119:Lysosomal-Associated Membrane Protein 2; D011068:Poly G; C026628:poly(dG); D012313:RNA; D004247:DNA