title: PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L-associated PI3K activity.
abstract: The Beclin1-VPS34 complex is recognized as a central node in regulating autophagy via interacting with diverse molecules such as ATG14L for autophagy initiation and UVRAG for autophagosome maturation. However, the underlying molecular mechanism that coordinates the timely activation of VPS34 complex is poorly understood. Here, we identify that PAQR3 governs the preferential formation and activation of ATG14L-linked VPS34 complex for autophagy initiation via two levels of regulation. Firstly, PAQR3 functions as a scaffold protein that facilitates the formation of ATG14L- but not UVRAG-linked VPS34 complex, leading to elevated capacity of PI(3)P generation ahead of starvation signals. Secondly, AMPK phosphorylates PAQR3 at threonine 32 and switches on PI(3)P production to initiate autophagosome formation swiftly after glucose starvation. Deletion of PAQR3 leads to reduction of exercise-induced autophagy in mice, accompanied by a certain degree of disaggregation of ATG14L-associated VPS34 complex. Together, this study uncovers that PAQR3 can not only enhance the capacity of pro-autophagy class III PI3K due to its scaffold function, but also integrate AMPK signal to activation of ATG14L-linked VPS34 complex upon glucose starvation.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Da-Qian
authors.initials: DQ
authors.lastname: Xu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Chen-Yao
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: De-Yi
authors.initials: DY
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Hui-Da
authors.initials: HD
authors.lastname: Wan
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zi-Long
authors.initials: ZL
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Gu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yong-Xian
authors.initials: YX
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Li
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China School of Life Sciences and Technology, Shanghai Tech University, Shanghai, China.
authors.forename: Kai-Yang
authors.initials: KY
authors.lastname: Man
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Zhi-Fei
authors.initials: ZF
authors.lastname: Wang
authors.affiliation: School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
authors.forename: Zun-Ji
authors.initials: ZJ
authors.lastname: Ke
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhi-Xue
authors.initials: ZX
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
authors.forename: Lu-Jian
authors.initials: LJ
authors.lastname: Liao
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China School of Life Sciences and Technology, Shanghai Tech University, Shanghai, China ychen3@sibs.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D012420:Running / Q000502:physiology; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C561107:Atg14 protein, mouse; D000071183:Autophagy-Related Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C523677:RKTG protein, mouse; D033921:Vesicular Transport Proteins; D058546:Class III Phosphatidylinositol 3-Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMPK; PAQR3; autophagy; class III PI3K; glucose starvation
references.citation: EMBO J. 2008 Apr 9;27(7):948-55
references.pmid: 18323777
references.citation: Cell Res. 2012 Apr;22(4):661-76
references.pmid: 21968647
references.citation: EMBO J. 2015 Apr 1;34(7):856-80
references.pmid: 25712477
references.citation: Genes Dev. 2011 Oct 1;25(19):1999-2010
references.pmid: 21979913
references.citation: Nat Commun. 2014 May 22;5:3920
references.pmid: 24849286
references.citation: Curr Biol. 2003 May 13;13(10):797-806
references.pmid: 12747827
references.citation: Am J Cancer Res. 2015 Aug 15;5(9):2562-8
references.pmid: 26609468
references.citation: Nat Rev Mol Cell Biol. 2007 Sep;8(9):741-52
references.pmid: 17717517
references.citation: Nat Protoc. 2009;4(10):1513-21
references.pmid: 19798084
references.citation: Trends Cell Biol. 2010 Jun;20(6):355-62
references.pmid: 20356743
references.citation: Cell Res. 2012 Mar;22(3):473-89
references.pmid: 22310240
references.citation: Nat Cell Biol. 2009 Apr;11(4):385-96
references.pmid: 19270696
references.citation: Mol Biol Cell. 2009 Apr;20(7):1981-91
references.pmid: 19211835
references.citation: J Biol Chem. 1996 Nov 1;271(44):27879-87
references.pmid: 8910387
references.citation: Nature. 2007 Jun 28;447(7148):1121-5
references.pmid: 17589504
references.citation: Annu Rev Genet. 2009;43:67-93
references.pmid: 19653858
references.citation: J Biol Chem. 2007 Dec 21;282(51):37124-33
references.pmid: 17940279
references.citation: Proc Natl Acad Sci U S A. 2011 May 10;108(19):7769-74
references.pmid: 21518905
references.citation: Cell. 2014 Dec 4;159(6):1263-76
references.pmid: 25480292
references.citation: Curr Opin Struct Biol. 2008 Oct;18(5):581-6
references.pmid: 18674618
references.citation: Science. 1993 Apr 2;260(5104):88-91
references.pmid: 8385367
references.citation: Nat Cell Biol. 2011 Feb;13(2):132-41
references.pmid: 21258367
references.citation: Eur J Biochem. 1990 Jan 12;187(1):183-90
references.pmid: 1967580
references.citation: Cell. 2013 Sep 12;154(6):1269-84
references.pmid: 24034250
references.citation: Mol Cell Proteomics. 2006 Apr;5(4):749-57
references.pmid: 16340016
references.citation: Autophagy. 2012 Apr;8(4):445-544
references.pmid: 22966490
references.citation: Science. 2011 Jan 28;331(6016):456-61
references.pmid: 21205641
references.citation: J Biol Chem. 2003 May 2;278(18):15461-4
references.pmid: 12604610
references.citation: Oncogene. 2010 Sep 30;29(39):5404-15
references.pmid: 20603618
references.citation: Nat Commun. 2012 Feb 07;3:662
references.pmid: 22314358
references.citation: Ann Oncol. 2014 Jul;25(7):1363-1372
references.pmid: 24799462
references.citation: Nat Med. 2013 Aug;19(8):983-97
references.pmid: 23921753
references.citation: Nature. 2006 Jun 15;441(7095):885-9
references.pmid: 16625204
references.citation: EMBO J. 2016 Mar 1;35(5):496-514
references.pmid: 26834238
references.citation: Nat Methods. 2010 Jun;7(6):429-34
references.pmid: 20508636
references.citation: Autophagy. 2010 May;6(4):506-22
references.pmid: 20505359
references.citation: Diabetes. 2013 Feb;62(2):444-56
references.pmid: 23086038
references.citation: Nat Cell Biol. 2010 Sep;12(9):814-22
references.pmid: 20811353
references.citation: Nat Cell Biol. 2009 Apr;11(4):468-76
references.pmid: 19270693
references.citation: Cell. 2003 Nov 26;115(5):577-90
references.pmid: 14651849
references.citation: N Engl J Med. 2013 May 9;368(19):1845-6
references.pmid: 23656658
references.citation: Mol Biol Cell. 2008 Dec;19(12):5360-72
references.pmid: 18843052
references.citation: J Biol Chem. 2001 Jun 1;276(22):19102-10
references.pmid: 11262401
references.citation: Cell. 2013 Jan 17;152(1-2):290-303
references.pmid: 23332761
references.citation: Nat Cell Biol. 2013 Jul;15(7):741-50
references.pmid: 23685627
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14348-53
references.pmid: 17724343
references.citation: Nat Cell Biol. 2007 Oct;9(10):1142-51
references.pmid: 17891140
references.citation: Nature. 2012 Jan 18;481(7382):511-5
references.pmid: 22258505
references.citation: Nat Rev Cancer. 2012 Apr 26;12(6):401-10
references.pmid: 22534666
references.citation: Cancer Res. 2011 Apr 15;71(8):2959-68
references.pmid: 21385899
references.citation: Mol Biol Cell. 2009 Apr;20(7):1992-2003
references.pmid: 19225151
references.citation: Nat Cell Biol. 2008 Jul;10(7):776-87
references.pmid: 18552835
references.citation: Biochem J. 2008 Sep 15;414(3):399-406
references.pmid: 18547165
references.citation: J Cell Biol. 2009 Feb 9;184(3):391-7
references.pmid: 19188490
references.citation: J Cell Biol. 2009 Sep 21;186(6):773-82
references.pmid: 19797076
references.citation: Science. 2012 Nov 16;338(6109):956-9
references.pmid: 23112296
references.citation: Nat Rev Mol Cell Biol. 2013 Dec;14(12):759-74
references.pmid: 24201109
references.citation: Autophagy. 2013 Oct;9(10):1491-9
references.pmid: 23884233
references.citation: J Cell Biol. 2013 Oct 28;203(2):299-313
references.pmid: 24165940