title: The lysosomal signaling anchor p18/LAMTOR1 controls epidermal development by regulating lysosome-mediated catabolic processes.
abstract: The lysosomal adaptor protein p18 is an essential anchor of a scaffolding complex for the mTORC1 and MAPK pathways, which play crucial roles in controlling cell growth and energy homeostasis. To elucidate the in vivo function of the p18-mediated pathway, we conditionally ablated p18 in the mouse epidermis. Mutant mice were born with severe defects in formation of the stratum corneum and died within 12 h after birth due to dehydration caused by loss of skin barrier function. Mutant epidermal cells can grow and differentiate into granular cells, but exhibit functional defects in corneocyte maturation. Electron microscopy identified abnormal immature cells, overlying the mutant granular cells, which accumulated autophagosomes, glycogen granules and dead nuclei. Cell culture analysis showed that loss of p18 attenuated lysosome function, resulting in accumulation of immature lysosomes and autophagosomes. Analyses of lysosome behavior revealed that p18 is required for functional interaction between lysosomes and target organelles including autophagosomes. These findings suggest that p18-mediated pathways control lysosome-mediated catabolic processes, which are crucial for the development of mouse epidermis.
authors.affiliation: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Taeko
authors.initials: T
authors.lastname: Soma-Nagae
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Nada
authors.forename: Mari
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Mori
authors.forename: Chitose
authors.initials: C
authors.lastname: Oneyama
authors.forename: Masato
authors.initials: M
authors.lastname: Okada
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001343:Autophagy / Q000502:physiology; D000078404:Epidermal Cells; D004817:Epidermis / Q000254:growth & development* / Q000378:metabolism*; D006706:Homeostasis; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054778:NM23 Nucleoside Diphosphate Kinases; C571152:late endosome-lysosome membrane adaptor p18, mouse; C517941:Nme2 protein, mouse
keywords: Autophagy; Epidermis; Lysosomes; mTORC1; p18