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PMID: 25925668 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Phosphorylation of the exchange factor DENND3 by ULK in response to starvation activates Rab12 and induces autophagy.

EMBO reports ·Vol. 16 ·No. 6 ·2015-06-00 ·Pages 709-18

Xu J, Fotouhi M, McPherson PS

Abstract

Unc-51-like kinases (ULKs) are the most upstream kinases in the initiation of autophagy, yet the molecular mechanisms underlying their function are poorly understood. We report a new role for ULK in the induction of autophagy. ULK-mediated phosphorylation of the guanine nucleotide exchange factor DENND3 at serines 554 and 572 upregulates its GEF activity toward the small GTPase Rab12. Through binding to LC3 and associating with LC3-positive autophagosomes, active Rab12 facilitates autophagosome trafficking, thus establishing a crucial role for the ULK/DENND3/Rab12 axis in starvation-induced autophagy.

Keywords
14‐3‐3 DENN domain GEF LC3 guanine nucleotide exchange factor
MeSH Terms
Autophagy Autophagy-Related Protein-1 Homolog Gene Knockdown Techniques Guanine Nucleotide Exchange Factors/genetics,metabolism HEK293 Cells Humans Intracellular Signaling Peptides and Proteins/genetics,metabolism Phagosomes/metabolism Phosphorylation Protein Serine-Threonine Kinases/genetics,metabolism Protein Transport RNA, Small Interfering rab GTP-Binding Proteins/genetics,metabolism
Chemicals
DENND3 protein, human Guanine Nucleotide Exchange Factors Intracellular Signaling Peptides and Proteins RNA, Small Interfering Autophagy-Related Protein-1 Homolog Protein Serine-Threonine Kinases ULK1 protein, human Ulk2 protein, human Rab12 protein, human rab GTP-Binding Proteins
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Xu Jie
Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University, Montreal, Quebec H3A 2B4, Canada peter.mcpherson@mcgill.ca jie.xu3@mail.mcgill.ca.
Fotouhi Maryam
Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University, Montreal, Quebec H3A 2B4, Canada.
McPherson Peter S
Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University, Montreal, Quebec H3A 2B4, Canada peter.mcpherson@mcgill.ca jie.xu3@mail.mcgill.ca.
References (31)
31 references, click to expand
  1. Large scale screening for novel rab effectors reveals unexpected broad Rab binding specificity.
    Mol Cell Proteomics. 2008 Jun;7(6):1031-42 PMID: 18256213
  2. Rab12 regulates mTORC1 activity and autophagy through controlling the degradation of amino-acid transporter PAT4.
    EMBO Rep. 2013 May;14(5):450-7 PMID: 23478338
  3. Shiga toxins induce autophagy leading to differential signalling pathways in toxin-sensitive and toxin-resistant human cells.
    Cell Microbiol. 2011 Oct;13(10):1479-96 PMID: 21722286
  4. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase.
    Nat Cell Biol. 2013 Jul;15(7):741-50 PMID: 23685627
  5. How do 14-3-3 proteins work?-- Gatekeeper phosphorylation and the molecular anvil hypothesis.
    FEBS Lett. 2002 Feb 20;513(1):53-7 PMID: 11911880
  6. The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy.
    J Cell Biol. 2010 Oct 4;191(1):155-68 PMID: 20921139
  7. DENN domain proteins: regulators of Rab GTPases.
    J Biol Chem. 2011 Apr 22;286(16):13791-800 PMID: 21330364
  8. Autophagy: renovation of cells and tissues.
    Cell. 2011 Nov 11;147(4):728-41 PMID: 22078875
  9. Early steps in autophagy depend on direct phosphorylation of Atg9 by the Atg1 kinase.
    Mol Cell. 2014 Feb 6;53(3):471-83 PMID: 24440502
  10. Small GTPase Rab12 regulates constitutive degradation of transferrin receptor.
    Traffic. 2011 Oct;12(10):1432-43 PMID: 21718402
  11. Rab GTPases as coordinators of vesicle traffic.
    Nat Rev Mol Cell Biol. 2009 Aug;10(8):513-25 PMID: 19603039
  12. The role of membrane-trafficking small GTPases in the regulation of autophagy.
    J Cell Sci. 2013 Mar 1;126(Pt 5):1059-69 PMID: 23620509
  13. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK.
    Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4788-93 PMID: 21383122
  14. Rab12 localizes to Shiga toxin-induced plasma membrane invaginations and controls toxin transport.
    Traffic. 2014 Jul;15(7):772-87 PMID: 24703428
  15. Rabs grab motors: defining the connections between Rab GTPases and motor proteins.
    Curr Opin Cell Biol. 2002 Feb;14(1):69-75 PMID: 11792547
  16. Discovery of Novel DENN Proteins: Implications for the Evolution of Eukaryotic Intracellular Membrane Structures and Human Disease.
    Front Genet. 2012 Dec 13;3:283 PMID: 23248642
  17. Diverse autophagosome membrane sources coalesce in recycling endosomes.
    Cell. 2013 Sep 12;154(6):1285-99 PMID: 24034251
  18. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1.
    Nat Cell Biol. 2011 Feb;13(2):132-41 PMID: 21258367
  19. The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs.
    Bioinformatics. 2013 Feb 15;29(4):499-503 PMID: 23329412
  20. The autophagic roles of Rab small GTPases and their upstream regulators: a review.
    Autophagy. 2014 Jul;10(7):1154-66 PMID: 24915298
  21. Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins.
    Autophagy. 2010 Aug;6(6):764-76 PMID: 20639694
  22. mTOR signaling in growth control and disease.
    Cell. 2012 Apr 13;149(2):274-93 PMID: 22500797
  23. Guidelines for the use and interpretation of assays for monitoring autophagy.
    Autophagy. 2012 Apr;8(4):445-544 PMID: 22966490
  24. Network organization of the human autophagy system.
    Nature. 2010 Jul 1;466(7302):68-76 PMID: 20562859
  25. Regulation of autophagy by the Rab GTPase network.
    Cell Death Differ. 2014 Mar;21(3):348-58 PMID: 24440914
  26. Genetic interactions between Drosophila melanogaster Atg1 and paxillin reveal a role for paxillin in autophagosome formation.
    Autophagy. 2008 Jan;4(1):37-45 PMID: 17952025
  27. Atg1-mediated myosin II activation regulates autophagosome formation during starvation-induced autophagy.
    EMBO J. 2011 Feb 16;30(4):636-51 PMID: 21169990
  28. TBC1D14 regulates autophagosome formation via Rab11- and ULK1-positive recycling endosomes.
    J Cell Biol. 2012 May 28;197(5):659-75 PMID: 22613832
  29. Dennd3 functions as a guanine nucleotide exchange factor for small GTPase Rab12 in mouse embryonic fibroblasts.
    J Biol Chem. 2014 May 16;289(20):13986-95 PMID: 24719330
  30. Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism.
    Mol Cell Biol. 2009 Jan;29(1):157-71 PMID: 18936157
  31. Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors.
    J Cell Biol. 2010 Oct 18;191(2):367-81 PMID: 20937701
Article Info
Journal
EMBO reports
Abbr.
EMBO Rep
ISSN
1469-3178
DOI
10.15252/embr.201440006
Email
peter.mcpherson@mcgill.ca
jie.xu3@mail.mcgill.ca
Published
2015-06-00
Epub
2015-00-29
Pages
709-18
Language
English
Region
England
NLM ID
100963049
PMCID
PMC4467855
Subset
IM
Grants
Canadian Institutes of Health Research · MOP-62684 · Canada
Corrections
CommentIn
PMID: 26177209
External Links
PubMed source DOI: 10.15252/embr.201440006 PMC Full Text View journal details
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