title: MicroRNAs-103/107 coordinately regulate macropinocytosis and autophagy.
abstract: Macropinocytosis, by which cells ingest large amounts of fluid, and autophagy, the lysosome-based catabolic process, involve vesicular biogenesis (early stage) and turnover (end stage). Much is known about early-stage events; however, our understanding of how the end stages of these processes are governed is incomplete. Here we demonstrate that the microRNA-103/107(miR-103/107) family, which is preferentially expressed in the stem cell-enriched limbal epithelium, coordinately regulates aspects of both these activities. Loss of miR-103/107 causes dysregulation of macropinocytosis with the formation of large vacuoles, primarily through up-regulation of Src, Ras, and Ankfy1. Vacuole accumulation is not a malfunction of early-stage autophagy; rather, miR-103/107 ensure proper end-stage autophagy by regulating diacylglycerol/protein kinase C and cyclin-dependent kinase 5 signaling, which enables dynamin to function in vacuole clearance. Our findings unveil a key biological function for miR-103/107 in coordinately suppressing macropinocytosis and preserving end-stage autophagy, thereby contributing to maintenance of a stem cell-enriched epithelium.
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, IL 60611.
authors.forename: Jong Kook
authors.identifier: http://orcid.org/0000-0002-5616-1124
authors.initials: JK
authors.lastname: Park
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, IL 60611.
authors.forename: Han
authors.initials: H
authors.lastname: Peng
authors.affiliation: Rush Medical Center, Chicago, IL 60615.
authors.forename: Julia
authors.initials: J
authors.lastname: Katsnelson
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, IL 60611.
authors.forename: Wending
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, IL 60611.
authors.forename: Nihal
authors.identifier: http://orcid.org/0000-0002-4552-5201
authors.initials: N
authors.lastname: Kaplan
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, IL 60611.|Department of Ophthalmology, The First Affiliated Hospital, Chinese PLA General Hospital, Beijing 100048, China.
authors.forename: Ying
authors.identifier: http://orcid.org/0000-0002-1650-6802
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Center for Advanced Microscopy and Nikon Imaging Center, Northwestern University, Chicago, IL 60611.
authors.forename: Joshua Z
authors.initials: JZ
authors.lastname: Rappoport
authors.affiliation: Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611.
authors.forename: CongCong
authors.identifier: http://orcid.org/0000-0001-5563-9096
authors.initials: C
authors.lastname: He
authors.affiliation: Department of Dermatology, Northwestern University, Chicago, IL 60611 r-lavker@northwestern.edu.
authors.forename: Robert M
authors.identifier: http://orcid.org/0000-0003-2570-9537
authors.initials: RM
authors.lastname: Lavker
mesh_terms: D000818:Animals; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D004075:Diglycerides / Q000378:metabolism; D034281:Dynamins / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D028044:Phosphate-Binding Proteins; D010873:Pinocytosis; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3 / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D015415:Biomarkers; D004075:Diglycerides; D034281:Dynamins; D008565:Membrane Proteins; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D028044:Phosphate-Binding Proteins; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C118719:ANKFY1 protein, human; C502070:MAP1LC3B protein, human; C544749:MIRN103 microRNA, human; C549045:MIRN107 microRNA, human; C122029:SHC3 protein, human