Phosphorylation of the exchange factor DENND3 by ULK in response to starvation activates Rab12 and induces autophagy.
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.
Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University, Montreal, Quebec H3A 2B4, Canada peter.mcpherson@mcgill.ca jie.xu3@mail.mcgill.ca.
Jie
J
Xu
Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University, Montreal, Quebec H3A 2B4, Canada.
Maryam
M
Fotouhi
Department of Neurology and Neurosurgery, Montreal Neurological Institute McGill University, Montreal, Quebec H3A 2B4, Canada peter.mcpherson@mcgill.ca jie.xu3@mail.mcgill.ca.
Peter S
PS
McPherson
D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D034741:RNA, Small Interfering; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
C000605578:DENND3 protein, human; D020662:Guanine Nucleotide Exchange Factors; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; C541703:Ulk2 protein, human; C000595432:Rab12 protein, human; D020691:rab GTP-Binding Proteins
14‐3‐3; DENN domain; GEF; LC3; guanine nucleotide exchange factor