title: Fine-tuning of ULK1 mRNA and protein levels is required for autophagy oscillation.
abstract: Autophagy is an intracellular degradation pathway whose levels are tightly controlled to secure cell homeostasis. Unc-51-like kinase 1 (ULK1) is a conserved serine-threonine kinase that plays a central role in the initiation of autophagy. Here, we report that upon autophagy progression, ULK1 protein levels are specifically down-regulated by the E3 ligase NEDD4L, which ubiquitylates ULK1 for degradation by the proteasome. However, whereas ULK1 protein is degraded, ULK1 mRNA is actively transcribed. Upon reactivation of mTOR-dependent protein synthesis, basal levels of ULK1 are promptly restored, but the activity of newly synthesized ULK1 is inhibited by mTOR. This prepares the cell for a new possible round of autophagy stimulation. Our results thus place NEDD4L and ULK1 in a key position to control oscillatory activation of autophagy during prolonged stress to keep the levels of this process under a safe and physiological threshold.
authors.affiliation: Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children's Hospital, 00146 Rome, Italy.|Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Francesca
authors.identifier: http://orcid.org/0000-0002-3039-4448
authors.initials: F
authors.lastname: Nazio
authors.affiliation: Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Marianna
authors.identifier: http://orcid.org/0000-0001-8106-9656
authors.initials: M
authors.lastname: Carinci
authors.affiliation: Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Cristina
authors.identifier: http://orcid.org/0000-0001-6725-2016
authors.initials: C
authors.lastname: Valacca
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Pamela
authors.identifier: http://orcid.org/0000-0003-3347-8345
authors.initials: P
authors.lastname: Bielli
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Flavie
authors.identifier: http://orcid.org/0000-0003-0285-7449
authors.initials: F
authors.lastname: Strappazzon
authors.affiliation: Freiburg Institute for Advanced Studies, University of Freiburg, 79104 Freiburg, Germany.|National Institute for Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico "L. Spallanzani," 00149 Rome, Italy.
authors.forename: Manuela
authors.identifier: http://orcid.org/0000-0002-7568-4713
authors.initials: M
authors.lastname: Antonioli
authors.affiliation: National Institute for Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico "L. Spallanzani," 00149 Rome, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Ciccosanti
authors.affiliation: Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Carlo
authors.identifier: http://orcid.org/0000-0001-7087-545X
authors.initials: C
authors.lastname: Rodolfo
authors.affiliation: Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.|Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, 00143 Rome, Italy.
authors.forename: Silvia
authors.identifier: http://orcid.org/0000-0003-0536-2484
authors.initials: S
authors.lastname: Campello
authors.affiliation: National Institute for Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico "L. Spallanzani," 00149 Rome, Italy.|Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.
authors.forename: Gian Maria
authors.identifier: http://orcid.org/0000-0003-4438-3325
authors.initials: GM
authors.lastname: Fimia
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, 00143 Rome, Italy.|Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Claudio
authors.identifier: http://orcid.org/0000-0003-2864-8266
authors.initials: C
authors.lastname: Sette
authors.affiliation: Department of Molecular Medicine, University of Padova, 35131 Padova, Italy.
authors.forename: Paolo
authors.identifier: http://orcid.org/0000-0001-7852-2173
authors.initials: P
authors.lastname: Bonaldo
authors.affiliation: Department of Pediatric Hematology and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesù Children's Hospital, 00146 Rome, Italy cecconi@cancer.dk.|Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.|Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
authors.forename: Francesco
authors.identifier: http://orcid.org/0000-0002-5614-4359
authors.initials: F
authors.lastname: Cecconi
mesh_terms: D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008954:Models, Biological; D000075702:Nedd4 Ubiquitin Protein Ligases; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D012333:RNA, Messenger; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases; D000071189:Autophagy-Related Protein-1 Homolog; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex; D008239:Lysine