title: MAPK15/ERK8 stimulates autophagy by interacting with LC3 and GABARAP proteins.
abstract: Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved catabolic process necessary for normal recycling of cellular constituents and for appropriate response to cellular stress. Although several genes belonging to the core molecular machinery involved in autophagosome formation have been discovered, relatively little is known about the nature of signaling networks controlling autophagy upon intracellular or extracellular stimuli. We discovered ATG8-like proteins (MAP1LC3B, GABARAP and GABARAPL1) as novel interactors of MAPK15/ERK8, a MAP kinase involved in cell proliferation and transformation. Based on the role of these proteins in the autophagic process, we demonstrated that MAPK15 is indeed localized to autophagic compartments and increased, in a kinase-dependent fashion, ATG8-like proteins lipidation, autophagosome formation and SQSTM1 degradation, while decreasing LC3B inhibitory phosphorylation. Interestingly, we also identified a conserved LC3-interacting region (LIR) in MAPK15 responsible for its interaction with ATG8-like proteins, for its localization to autophagic structures and, consequently, for stimulation of the formation of these compartments. Furthermore, we reveal that MAPK15 activity was induced in response to serum and amino-acid starvation and that this stimulus, in turn, required endogenous MAPK15 expression to induce the autophagic process. Altogether, these results suggested a new function for MAPK15 as a regulator of autophagy, acting through interaction with ATG8 family proteins. Also, based on the key role of this process in several human diseases, these results supported the use of this MAP kinase as a potential novel therapeutic target.
authors.affiliation: Istituto Toscano Tumori-Core Research Laboratory, Signal Transduction Unit, AOU Senese, Siena, Italy.
authors.forename: David
authors.initials: D
authors.lastname: Colecchia
authors.forename: Angela
authors.initials: A
authors.lastname: Strambi
authors.forename: Sveva
authors.initials: S
authors.lastname: Sanzone
authors.forename: Carlo
authors.initials: C
authors.lastname: Iavarone
authors.forename: Matteo
authors.initials: M
authors.lastname: Rossi
authors.forename: Claudia
authors.initials: C
authors.lastname: Dall'Armi
authors.forename: Federica
authors.initials: F
authors.lastname: Piccioni
authors.forename: Arturo
authors.initials: A
authors.lastname: Verrotti di Pianella
authors.forename: Mario
authors.initials: M
authors.lastname: Chiariello
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D055162:Biocatalysis; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000737:chemistry / Q000378:metabolism*; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D059748:Proteolysis; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D003598:Cytoskeletal Proteins; C480861:GABARAP protein, mouse; D006360:Heat-Shock Proteins; C480860:Map1lc3b protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; C456320:MAPK15 protein, human