title: Inhibition of autophagy through MAPK14-mediated phosphorylation of ATG5.
abstract: Autophagy is a catabolic mechanism that is important for many biological processes such as cell homeostasis, development and immunity. Though many molecular components of the autophagy pathway have been identified, the signaling pathways regulating the activity of essential autophagy mediators are still poorly defined. We recently demonstrated that the mitogen-activated protein kinase MAPK14 (p38α), when activated by the GADD45B (Gadd45β)-MAP3K4 (MEKK4) signaling complex (but not other MAPK14 activators), is directed to autophagosomes. Therefore, we demonstrated for the first time that MAPK14 operates at this subcellular compartment. Importantly, activation of MAPK14 impairs autophagosome-lysosome fusion and, thus, autophagy. This was demonstrated by increased autophagic flux in MAPK14-deficient as well as in GADD45B-deficient cells. Moreover, we identified a novel post-translational modification of the crucial autophagy mediator ATG5, since MAPK14 directly phosphorylates ATG5 at threonine 75, which is evolutionarily conserved from yeast to human. Using ATG5-deficient cells, which we reconstituted with either a phosphorylation-defective or a phospho-mimetic mutant of ATG5, we demonstrated that phosphorylation of ATG5 results in impaired autophagy.
authors.affiliation: Systems-oriented Immunology and Inflammation Research, Institute of Molecular and Clinical Immunology, Otto-von-Guericke-University Magdeburg and Department of Immune Control, Helmholtz Center for Infection Research, Braunschweig, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Höcker
authors.forename: Alisha
authors.initials: A
authors.lastname: Walker
authors.forename: Ingo
authors.initials: I
authors.lastname: Schmitz
mesh_terms: D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D048308:Mitogen-Activated Protein Kinase 14