Affinage

ULK1

Serine/threonine-protein kinase ULK1 · UniProt O75385

Length
1050 aa
Mass
112.6 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ULK1 is a serine/threonine kinase that functions as the apical initiator of autophagy and additionally regulates ER-to-Golgi trafficking, stress granule clearance, focal adhesion dynamics, and necroptosis. Under nutrient sufficiency, mTORC1 phosphorylates ULK1 at Ser757 to block AMPK binding and prevent activation; energy stress relieves this inhibition, and AMPK phosphorylates ULK1 at Ser317/Ser777 to activate the kinase, which then phosphorylates Beclin-1 (Ser14), ATG14L, Atg9, and BNIP3 (Ser17) to drive phagophore nucleation, membrane expansion, and selective mitophagy (PMID:21258367, PMID:23685627, PMID:24440502, PMID:34654847). ULK1 activation requires FIP200/Atg11-mediated dimerization and cis-autophosphorylation, is positively tuned by GABARAP binding and PRMT5-catalyzed Arg170 methylation, and is negatively regulated by Hsp90 chaperoning, TRIM27- and NEDD4L-mediated K48-linked ubiquitination, ERK1/2–β-TrCP-dependent degradation, and DRAK2 phosphorylation at Ser56 (PMID:32909946, PMID:35246531, PMID:37453059, PMID:35670107, PMID:38324636). Beyond autophagy, ULK1 phosphorylates SEC16A and Sec23A to remodel ER exit sites, VCP/p97 to promote stress granule disassembly, paxillin to inhibit focal adhesion phase separation, RIPK1 to suppress necroptosis, and interacts with SARM1 to promote axonal degeneration (PMID:27203176, PMID:30979586, PMID:37846507, PMID:32320653, PMID:36375051).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2005 High

    Establishing that Atg17 scaffolding of the Atg1-Atg13 complex is essential for Atg1 kinase activity and autophagosome formation answered how the core initiation complex assembles and why its integrity matters for autophagy.

    Evidence Co-IP, two-hybrid, kinase assay, and point-mutant analysis in yeast

    PMID:15743910

    Open questions at the time
    • Mammalian FIP200 (Atg17 functional analog) architecture not yet resolved
    • Stoichiometry of the complex in vivo unknown
  2. 2008 High

    Demonstration that UNC-51/Atg1 phosphorylates the kinesin adaptor UNC-76 to enable synaptic vesicle axonal transport established that Atg1-family kinases have autophagy-independent neuronal functions.

    Evidence In vitro kinase assay and phospho-mutant rescue in Drosophila

    PMID:19056884

    Open questions at the time
    • Whether mammalian ULK1 has equivalent axonal transport substrates was untested
    • Mechanism linking kinase activity to motor-cargo assembly remained unclear
  3. 2009 High

    Showing that TORC1 directly phosphorylates Atg13 to inhibit Atg1 activation, and that unphosphorylatable Atg13 bypasses TORC1, defined the nutrient-sensing input controlling the autophagy initiation complex.

    Evidence In vitro TORC1 kinase assay, mutagenesis, and epistasis in yeast

    PMID:19995911

    Open questions at the time
    • Direct mTOR phosphorylation sites on mammalian ULK1 not yet mapped
  4. 2011 High

    Identification of AMPK as an activating kinase (Ser317/Ser777) and mTOR as an inhibitory kinase (Ser757) of mammalian ULK1 established the dual nutrient/energy-sensing switch controlling autophagy initiation.

    Evidence In vitro kinase assays, mutagenesis, co-IP, and AMPK/ULK1 knockout models across two independent studies

    PMID:21205641 PMID:21258367

    Open questions at the time
    • Whether additional kinases contribute to ULK1 regulation under other stress conditions was unknown
    • Precise structural basis for mTOR disruption of AMPK-ULK1 interaction not determined
  5. 2013 High

    Discovery that active ULK1 phosphorylates Beclin-1 at Ser14 to stimulate ATG14L-VPS34 lipid kinase complexes connected ULK1 activation to the PI3P-generating step of phagophore nucleation.

    Evidence In vitro kinase assay, mutagenesis, VPS34 lipid kinase activity assay, replicated in C. elegans

    PMID:23685627

    Open questions at the time
    • Other ULK1 substrates within the VPS34 complex not yet identified
    • Quantitative relationship between Beclin-1 phosphorylation and PI3P output unknown
  6. 2014 High

    Structural reconstitution of the Atg1-Atg13-Atg17-Atg31-Atg29 pentamer and demonstration that Atg1 phosphorylates Atg9 to recruit Atg8/Atg18 defined the architecture and immediate downstream output of the initiation complex on membranes.

    Evidence HDX-MS, analytical ultracentrifugation for the pentamer; peptide array substrate screen and mutagenesis for Atg9 phosphorylation

    PMID:24440502 PMID:25139988

    Open questions at the time
    • Whether mammalian ATG9A is similarly a direct ULK1 substrate was unconfirmed
    • Membrane geometry of the dimer-of-pentamers not resolved
  7. 2016 High

    Identification of SEC16A as a ULK1/2 substrate demonstrated a non-autophagic function: ULK1 regulates ER exit site assembly and ER-to-Golgi trafficking, with loss causing UPR activation; concurrent discovery that Atg17 tethers Atg9 vesicles further clarified initiation complex membrane engagement.

    Evidence Proteomics, phosphomimetic rescue, conditional KO mice (SEC16A); in vitro membrane tethering with purified components (Atg9 vesicles)

    PMID:26753620 PMID:27203176

    Open questions at the time
    • Relative contribution of ULK1 vs ULK2 to ER-to-Golgi trafficking unclear
    • Whether SEC16A phosphorylation and autophagy substrates are regulated by different ULK1 pools unknown
  8. 2016 Medium

    Discovery that NEDD4L ubiquitinates ULK1 for proteasomal degradation during prolonged stress revealed that ULK1 protein turnover is a timer limiting autophagy duration.

    Evidence Co-IP, ubiquitination assay, proteasome inhibitor experiments

    PMID:27932573

    Open questions at the time
    • Specific ubiquitin chain type and lysine sites on ULK1 targeted by NEDD4L not fully mapped
    • Whether NEDD4L-mediated degradation is the dominant degradation pathway was unclear
  9. 2017 Medium

    ULK1 phosphorylation of Sec23A and of AMPK β1 (Ser108) expanded the substrate repertoire: Sec23A phosphorylation diverts COPII trafficking during autophagy, while AMPK β1 phosphorylation creates a positive feedback sensitizing AMPK to allosteric activators.

    Evidence In vitro kinase assays, mass spectrometry, mutagenesis, pharmacological analysis

    PMID:28486929 PMID:28924239

    Open questions at the time
    • Physiological contribution of ULK1-AMPK feedback loop relative to canonical LKB1/CaMKKβ activation unclear
    • Whether Sec23A phosphorylation occurs in all cell types or is context-specific unknown
  10. 2018 Medium

    Identification of USP20 as a deubiquitinase stabilizing ULK1 and of mineralocorticoid receptor as a ULK1 substrate (Ser843) broadened ULK1's regulatory network to include deubiquitination-mediated stabilization and endocrine signaling.

    Evidence Co-IP and ubiquitination assays (USP20); high-throughput kinase screen, in vitro kinase assay, ULK1/2 DKO MEFs (MR)

    PMID:29487085 PMID:30021155

    Open questions at the time
    • Relative importance of USP20 vs other DUBs for ULK1 stability unknown
    • In vivo physiological role of MR Ser843 phosphorylation by ULK1 not fully characterized
  11. 2019 High

    NDP52 was shown to recruit and locally activate ULK1 on cargo independently of AMPK/mTOR, establishing a cargo-driven, receptor-mediated initiation pathway for selective autophagy; concurrently, GABARAPs were found to positively regulate ULK1 activity while LC3 subfamily members negatively regulate it, and ULK1/2 were shown to phosphorylate VCP/p97 to promote stress granule disassembly.

    Evidence CID assay, CRISPR KO, live imaging (NDP52); genome editing and reconstitution with ATG8 members (GABARAP/LC3); VCP ATPase assay and ULK1/2 DKO mice with vacuolar myopathy (VCP)

    PMID:30853401 PMID:30979586 PMID:31208283

    Open questions at the time
    • Structural basis for NDP52-FIP200-membrane allosteric coupling not yet resolved
    • Whether VCP phosphorylation by ULK1 is relevant to neurodegenerative disease in humans unknown
    • Full spectrum of ATG8 member-specific effects on ULK1 not delineated
  12. 2020 High

    Multiple studies resolved ULK1 activation mechanism and expanded non-autophagy substrates: FIP200/Atg11-driven dimerization enables cis-autophosphorylation of Atg1; NDP52 allosterically triggers FIP200 membrane binding; ERK1/2 phosphorylation promotes ULK1 degradation via β-TrCP; ULK1 phosphorylates RIPK1 to suppress necroptosis; and Atg1 phosphorylates Yorkie/YAP to inhibit growth signaling.

    Evidence Chemical dimerization and genetic rescue in S. pombe; HDX-MS and GUV reconstitution (NDP52-FIP200); co-IP and ubiquitination assays (ERK-β-TrCP); in vitro kinase assay and cell death assays (RIPK1); in vitro kinase and Drosophila genetics (Yorkie)

    PMID:32032548 PMID:32320653 PMID:32773036 PMID:32909946 PMID:33213267

    Open questions at the time
    • Whether dimerization-dependent activation applies identically to mammalian ULK1 not demonstrated
    • Physiological contexts where ULK1-RIPK1 axis predominates over canonical RIPK1 regulation unknown
  13. 2021 Medium

    A wave of studies identified new ULK1 regulatory inputs and substrates: DAPK3 phosphorylates ULK1 Ser556 to promote complex formation; GSK3B phosphorylates ULK1 S405/S415 to facilitate LC3/GABARAP binding; ULK1 phosphorylates BNIP3/BNIP3L to promote mitophagy; ULK1 phosphorylates striatin to activate PP2A in a feedback loop; and Atg8-PE on growing membranes activates Atg1, which phosphorylates Atg13 for complex turnover and inhibits the Atg8 conjugation machinery as negative feedback.

    Evidence In vitro kinase assays, mutagenesis, autophagy flux assays, reconstitution with purified components across multiple independent studies

    PMID:33037394 PMID:33654220 PMID:34592149 PMID:34654847 PMID:34798055

    Open questions at the time
    • Integration of DAPK3, GSK3B, and AMPK inputs into a unified signaling model not achieved
    • Whether PP2A-ULK1 feedback operates in all tissues unknown
    • Quantitative contribution of each regulatory kinase to ULK1 activation under physiological conditions not determined
  14. 2022 High

    PRMT5-catalyzed arginine methylation (Arg170) was identified as a novel activating modification reversed by KDM5C, linking hypoxia to ULK1 autophosphorylation and autophagy; TRIM27 was found to impose dual-layer ubiquitin control—K48-linked degradation basally and STK38L-dependent hyper-ubiquitination during starvation to restrain autophagy amplitude.

    Evidence In vitro methyltransferase and kinase assays, mass spectrometry, mutagenesis (PRMT5); in vitro ubiquitination, kinase assay, mutagenesis, and mouse KO (TRIM27)

    PMID:35246531 PMID:35670107

    Open questions at the time
    • Whether arginine methylation and ubiquitination crosstalk on ULK1 is not known
    • Identity of the demethylase under normoxic conditions beyond KDM5C not fully resolved
  15. 2023 High

    Single-molecule imaging revealed ULK1 forms large ER-associated nanoclusters upon starvation; mechanistic studies showed ULK1 phosphorylates LDHA to produce lactate that lactylates VPS34, and ULK1 phosphorylates paxillin to disrupt focal adhesion phase separation; Hsp90 was identified as both a ULK1 inhibitor and substrate, establishing a bidirectional activation switch; ULK1 interaction with SARM1 was linked to axonal degeneration.

    Evidence PALM single-molecule imaging; in vitro kinase and acylation mass spectrometry (LDHA-VPS34); LLPS and traction force microscopy (paxillin); reciprocal kinase/ATPase assays (Hsp90); co-IP, inhibitor, and mouse SCI model (SARM1)

    PMID:36375051 PMID:37267363 PMID:37453059 PMID:37774021 PMID:37846507

    Open questions at the time
    • How nanocluster size translates to autophagy output is not quantitatively modeled
    • Whether LDHA-lactylation pathway is relevant in tissues with low glycolytic flux unknown
    • Whether SARM1 is a ULK1 kinase substrate or only a binding partner is unresolved
  16. 2024 High

    ZDHHC13-mediated palmitoylation of ULK1 was shown to be required for its translocation to autophagosome formation sites and ATG14L phosphorylation; DRAK2 phosphorylation of ULK1 at Ser56 was found to promote ULK1 ubiquitination and suppress autophagy in pancreatic β cells, linking ULK1 regulation to metabolic disease.

    Evidence Palmitoylation assay, mutagenesis, live-cell imaging (ZDHHC13); phosphoproteomics, in vitro kinase assay, conditional KO mice in primary islets (DRAK2)

    PMID:38324636 PMID:39169022

    Open questions at the time
    • Palmitoylation site(s) on ULK1 not identified
    • Whether DRAK2-ULK1 axis is relevant to human type 2 diabetes requires clinical validation
    • Interplay between palmitoylation and ubiquitination on ULK1 membrane targeting not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified quantitative model integrating the >10 identified kinase, ubiquitin, methylation, and palmitoylation inputs into a coherent signaling logic for ULK1 activation thresholds in different tissues and stress contexts remains to be built.
  • No integrative systems-level model of ULK1 PTM crosstalk exists
  • Structural basis for full-length mammalian ULK1 complex not resolved
  • Tissue-specific roles of ULK1 non-autophagy substrates (paxillin, MR, LDHA, SARM1) lack in vivo validation in human systems

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 18 GO:0140657 ATP-dependent activity 3
Localization
GO:0031410 cytoplasmic vesicle 3 GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 2
Pathway
R-HSA-9612973 Autophagy 18 R-HSA-162582 Signal Transduction 6 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9609507 Protein localization 2 R-HSA-1640170 Cell Cycle 1
Partners
AMPKATG13BECN1FIP200HSP90NDP52SARM1TRIM27
Complex memberships
Atg1-Atg13-Atg17-Atg31-Atg29 pentamerULK1-ATG13-FIP200-ATG101 complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 AMPK directly phosphorylates ULK1 at Ser317 and Ser777 to activate it under glucose starvation, promoting autophagy. Conversely, mTOR phosphorylates ULK1 at Ser757 under nutrient sufficiency, disrupting the ULK1-AMPK interaction and preventing ULK1 activation. In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, genetic knockout models Nature cell biology High 21205641 21258367
2010 AMPK phosphorylates ULK1 (and ULK2) as conserved substrates; loss of AMPK or ULK1 in mammalian liver results in aberrant p62 accumulation and defective mitophagy; ULK1 mutant unable to be phosphorylated by AMPK cannot support mitochondrial homeostasis or cell survival during starvation. AMPK substrate screen, genetic analysis in mouse liver and C. elegans, reconstitution with phospho-mutant ULK1 Science High 21205641
2013 Activated ULK1 directly phosphorylates Beclin-1 at Ser14 following amino-acid starvation or mTOR inhibition, thereby enhancing the activity of ATG14L-containing VPS34 lipid kinase complexes and driving autophagy induction. In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, VPS34 lipid kinase activity assay Nature cell biology High 23685627
2019 NDP52 recruits and focally activates the ULK1 complex on cargo (mitochondria or peroxisomes) to initiate selective autophagy; this requires NDP52 interaction with FIP200/ULK1 complex facilitated by TBK1; focal ULK1 activation occurs independently of AMPK and mTOR. Chemically inducible dimerization (CID) assay, CRISPR KO, live imaging Molecular cell High 30853401
2009 In yeast, TORC1 directly phosphorylates Atg13 (the ULK1 complex scaffolding subunit) at multiple Ser residues; expression of unphosphorylatable Atg13 bypasses TORC1 to activate Atg1 kinase and induce autophagy under nutrient-rich conditions. In vitro kinase assay, site-directed mutagenesis, genetic epistasis in yeast Molecular and cellular biology High 19995911
2005 Atg17 physically associates with the Atg1-Atg13 complex through Atg13; this interaction is enhanced under starvation and is required for normal autophagosome size and Atg1 kinase activity; a point mutant of Atg17 (C24R) with reduced Atg13 affinity impairs Atg1 kinase activity and autophagy. Co-immunoprecipitation, two-hybrid analysis, kinase assay, yeast genetics Molecular biology of the cell High 15743910
2014 Atg1/ULK1 kinase directly phosphorylates the multimembrane-spanning protein Atg9; phosphorylated Atg9 recruits Atg8 and Atg18 to the autophagosome formation site and promotes isolation membrane expansion. Consensus peptide array substrate screen, in vitro kinase assay, mutagenesis, fluorescence microscopy Molecular cell High 24440502
2016 ULK1 and ULK2 phosphorylate SEC16A to regulate assembly of ER exit sites and ER-to-Golgi trafficking of specific cargo, independently of ATG13; loss of ULK1/2 causes defective ER-to-Golgi trafficking that activates the unfolded protein response. Unbiased proteomics (interaction partner identification), phosphorylation assay, phosphomimetic rescue, conditional KO mice Molecular cell High 27203176
2016 ULK1 is ubiquitylated by the E3 ligase NEDD4L during autophagy progression, targeting it for proteasomal degradation, which limits the amplitude and duration of autophagy during prolonged stress. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor experiments, protein stability assay Journal of cell biology Medium 27932573
2019 ULK1 and ULK2 localize to stress granules and phosphorylate VCP/p97, increasing its ATPase activity and ability to disassemble stress granules; loss of ULK1/2 causes vacuolar myopathy with TDP-43-positive inclusions in mice. Phosphorylation assay, VCP ATPase activity assay, localization by imaging, mouse KO with histopathological phenotype Molecular cell High 30979586
2017 ULK1 phosphorylates Sec23A (a COPII vesicle coat component) at Ser207, Ser312, and Thr405; phosphorylation of Sec23A reduces its interaction with Sec31A, causing ERES aggregation and inhibition of ER-to-Golgi cargo transport during autophagy induction. In vitro kinase assay, mass spectrometry, phospho-mutant analysis, co-immunoprecipitation BMC cell biology Medium 28486929
2008 UNC-51/ATG1 (Drosophila ortholog) phosphorylates the kinesin adaptor UNC-76 on Ser143; phosphorylated UNC-76 binds Synaptotagmin-1, enabling motor-cargo assembly for synaptic vesicle axonal transport; phospho-defective UNC-76 fails to rescue axonal transport defects. In vitro kinase assay, genetic epistasis in Drosophila, phospho-defective/mimetic rescue experiments Genes & development High 19056884
2016 The Atg1-kinase complex tethers Atg9-vesicles to initiate autophagy; the scaffolding protein Atg17 specifically recognizes Atg9 to recruit Atg9-vesicles, an activity regulated by Atg31/Atg29 and restored by Atg1-Atg13 engagement. In vitro reconstitution with purified components, membrane tethering assay Nature communications High 26753620
2014 The Atg1-Atg13 subcomplex forms with ~100 nM affinity via mutually interacting domains; this complex then binds the Atg17-Atg31-Atg29 scaffold with ~10 μM affinity through Atg13, forming a dimer-of-pentamers during starvation. Hydrogen-deuterium exchange mass spectrometry, analytical ultracentrifugation, structural reconstitution PNAS High 25139988
2020 NDP52 allosterically stimulates membrane binding by the FIP200 coiled-coil of the ULK1 complex; HDX-MS mapped NDP52 and membrane binding sites to distinct FIP200 coiled-coil regions; GUV reconstitution confirmed NDP52-triggered membrane recruitment. HDX-MS, electron microscopy, giant unilamellar vesicle (GUV) reconstitution eLife High 32773036
2020 MAPK1/ERK2-MAPK3/ERK1 phosphorylation of ULK1 promotes its interaction with BTRC (β-TrCP) and subsequent K48-linked ubiquitination and proteasomal degradation, attenuating mitophagy. Co-immunoprecipitation, ubiquitination assay, kinase assay, proteasome inhibition Autophagy Medium 33213267
2021 ULK1 phosphorylates BNIP3 at Ser17 (adjacent to its LIR motif), promoting BNIP3-LC3 interaction and mitophagy; ULK1 similarly phosphorylates BNIP3L at Ser35; ULK1 interaction also stabilizes BNIP3 by limiting its proteasomal turnover. In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, mitophagy flux assay Scientific reports Medium 34654847
2021 DAPK3 directly phosphorylates ULK1 at Ser556 by in vitro kinase assay, facilitating ULK1 complex formation and VPS34 complex activation; this phosphorylation is required for DAPK3-induced autophagy. Mass spectrometry, in vitro kinase assay, immunoprecipitation, autophagy flux assay Cell death and differentiation Medium 33037394
2021 GSK3B directly interacts with and phosphorylates ULK1 at S405 and S415 within the GABARAP-interacting region following insulin withdrawal, facilitating ULK1 interaction with MAP1LC3B and GABARAPL1 and inducing autophagy flux; phospho-defective mutants fail to induce autophagy. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, autophagy flux assay Experimental and molecular medicine Medium 33654220
2022 TRIM27 polyubiquitinates ULK1 at K568 and K571 with K48-linked chains for proteasomal degradation under basal conditions; during starvation, TRIM27 also catalyzes non-degradative K6/K11-linked ubiquitination of STK38L, activating it to phosphorylate ULK1 at Ser495, which triggers TRIM27-mediated hyper-ubiquitination of ULK1 to restrain autophagy amplitude. Co-immunoprecipitation, in vitro ubiquitination assay, site-directed mutagenesis, kinase assay, mouse KO EMBO journal High 35670107
2018 USP20 deubiquitinase binds ULK1 and removes K48-linked ubiquitin, stabilizing ULK1 by preventing its lysosomal degradation; USP20 depletion reduces ULK1 protein levels and inhibits starvation-induced autophagosome formation. Co-immunoprecipitation, ubiquitination assay, RNA interference, LC3 puncta formation assay EMBO reports Medium 29487085
2022 PRMT5 catalyzes symmetrical dimethylation of ULK1 at Arg170 (R170me2s), a modification removed by KDM5C; under hypoxia, reduced KDM5C activity causes accumulation of R170me2s, which promotes ULK1 autophosphorylation at Thr180, activating ULK1 and inducing autophagy. In vitro methyltransferase assay, mass spectrometry, mutagenesis, autophagy flux assay Nature communications High 35246531
2023 ULK1 directly interacts with and phosphorylates LDHA at Ser196 under nutrient deprivation, promoting lactate production; lactate in turn lactylates VPS34 at Lys356 and Lys781 (via KAT5/TIP60), enhancing VPS34 lipid kinase activity and autophagic flux. Co-immunoprecipitation, in vitro kinase assay, acylation mass spectrometry, VPS34 kinase activity assay Science advances Medium 37267363
2019 GABARAPs positively regulate ULK1 activity and phagophore formation; LC3 subfamily negatively regulates ULK1 activity; ULK1 LIR motif mutation by genome editing drastically reduces ULK1 activity and autophagic flux; ATG13-ATG8 interaction similarly promotes ULK1 activity. CRISPR/Cas9 genome editing, TALEN, reconstitution with individual ATG8 members, ULK1 kinase activity assay Autophagy High 31208283
2020 ULK1 phosphorylates RIPK1 at multiple sites (especially S357 in the intermediate domain), reducing RIPK1 complex IIb/necrosome assembly and TNF-induced necroptotic cell death; ULK1 loss enhances TNF-induced cell death. In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, cell death assay Cell reports Medium 32320653
2017 ULK1 phosphorylates the AMPK β1 regulatory subunit at Ser108 in cells, sensitizing AMPK to allosteric drugs (salicylate, A-769662); this depends on β1 myristoylation and energy stress, and enables AMPK signaling partially independent of Thr172 phosphorylation. Cellular kinase assay, mass spectrometry, genetic knockdown, pharmacological analysis Nature communications Medium 28924239
2018 ULK1 is the principal kinase that phosphorylates mineralocorticoid receptor (MR) at Ser843 in the ligand-binding domain, as identified by high-throughput kinase screen confirmed by in vitro kinase assay, mass spectrometry, and ULK1/2 double-KO MEFs; angiotensin II via mTOR inhibits ULK1 to modulate MR activity. High-throughput kinase screen, in vitro kinase assay, mass spectrometry, siRNA knockdown, double-KO MEFs Cell reports High 30021155
2021 ULK1 directly phosphorylates the regulatory PP2A subunit striatin, activating PP2A; this creates a positive feedback loop promoting autophagy-dependent protein turnover; ULK1 is also itself a PP2A substrate. Phosphoproteomics, in vitro kinase assay, PP2A activity assay Cell reports Medium 34592149
2019 TRAF3 forms a complex with TRAF2 and cIAP1 and mediates K48-linked ubiquitination and degradation of ULK1; ULK1 depletion promotes inflammasome activation and pyroptosis in macrophages. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, caspase-1 activation assay FASEB journal Medium 32275117
2024 ULK1 is palmitoylated by palmitoyltransferase ZDHHC13 upon autophagy induction, which is required for ULK1 translocation to autophagosome formation sites; palmitoylated ULK1 enhances phosphorylation of ATG14L to activate PI3-kinase. Palmitoylation assay, site-directed mutagenesis, live-cell imaging, ATG14L phosphorylation assay Nature communications High 39169022
2023 Hsp90 forms a complex with ULK1 that suppresses ULK1 kinase activity; upon autophagy induction, ULK1 phosphorylates a conserved serine in the Hsp90 amino domain, inhibiting Hsp90 ATPase activity, causing Hsp90:ULK1 complex dissociation and ULK1 activation. Co-immunoprecipitation, in vitro kinase assay, ATPase assay, mutagenesis Cell reports High 37453059
2020 In fission yeast, Atg1/ULK1 kinase activity requires Atg11 (FIP200 ortholog), which drives Atg1 dimerization via its homodimerization domain; Atg1 activation in the dimer proceeds via cis-autophosphorylation; artificially dimerizing Atg1 bypasses the need for Atg11. Kinase assay, domain truncation, chemical dimerization, genetic rescue in S. pombe eLife High 32909946
2020 CDK1/cyclin B phosphorylates both ULK1 and ATG13 during mitosis; this CDK1-induced phosphorylation promotes mitotic autophagy and cell cycle progression; double KO of ULK1 and ATG13 blocks cell cycle progression. Mass spectrometry, site-directed mutagenesis, cell cycle synchronization, double KO mouse and cell models PLOS biology Medium 32516310
2021 Atg1 (yeast) is activated by lipidated Atg8 (Atg8-PE) along the growing autophagosomal membrane; Atg1-dependent phosphorylation of Atg13 triggers Atg1 complex dissociation enabling rapid subunit turnover; Atg1 also phosphorylates and inhibits the Atg8-specific E2 and E3 ligases as a negative feedback. In vitro reconstitution, phosphorylation assay, cell-based approaches Molecular cell High 34798055
2023 ULK1 physically interacts with SARM1 via SARM1's SAM domains; this interaction increases upon neurite damage and promotes SARM1 accumulation in injured axons; ULK1 inhibition or knockdown attenuates neurite fragmentation and reduces SARM1 puncta accumulation. Co-immunoprecipitation, domain mapping, ULK1 inhibitor, shRNA knockdown, mouse SCI model PNAS Medium 36375051
2020 Atg1/ULK1 phosphorylates Yorkie (YAP ortholog in Drosophila) at S74 and S97; ULK1 phosphorylates Yorkie in vitro; in vivo Atg1 gain-of-function raises Yorkie phosphorylation and inhibits its growth-promoting activity; this function is independent of Atg13. In vitro kinase assay, in vivo Drosophila genetics, phosphorylation-site mutagenesis Developmental cell Medium 32032548
2023 ULK1 forms large nanoscopic clusters (up to 161 molecules) at the ER upon amino acid starvation; ULK1 activity is dispensable for initial clustering but necessary for cluster expansion that involves Atg14, Atg16, and LC3B recruitment and requires Vps34 activity. Quantitative photoactivated localization microscopy (PALM), single-molecule imaging, CRISPR KO, ULK1 kinase inhibition Science advances High 37774021
2023 ULK1/2 phosphorylate paxillin (PXN) at S32 and S119, weakening PXN homotypic interactions and liquid-liquid phase separation, impairing focal adhesion assembly and inhibiting actin stress fiber formation and cell migration; ULK1/2 and FAK/Src have opposing effects on PXN phosphorylation at adjacent residues. In vitro kinase assay, mutagenesis, LLPS assay, focal adhesion imaging, traction force microscopy EMBO reports High 37846507
2024 DRAK2 directly phosphorylates ULK1 at Ser56, which induces ULK1 ubiquitylation and suppresses autophagy in pancreatic β cells; ULK1-S56A mutation preserves mitochondrial function and insulin secretion against lipotoxicity. Phosphoproteome analysis, in vitro kinase assay, site-directed mutagenesis, conditional KO mice, ubiquitylation assay Science translational medicine High 38324636
2015 The chaperone-like protein p32 forms a complex with ULK1 and protects it from K48-linked polyubiquitination and proteasomal degradation; p32 depletion impairs starvation-induced autophagy and mitophagy, rescued by ULK1 re-expression. Co-immunoprecipitation, ubiquitination assay, proteasome inhibition, autophagy/mitophagy flux assay Cell death and differentiation Medium 25909887

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature cell biology 5883 21258367
2010 Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science (New York, N.Y.) 2147 21205641
2013 ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nature cell biology 1290 23685627
2017 The mammalian ULK1 complex and autophagy initiation. Essays in biochemistry 643 29233870
2019 Spatiotemporal Control of ULK1 Activation by NDP52 and TBK1 during Selective Autophagy. Molecular cell 389 30853401
2009 Tor directly controls the Atg1 kinase complex to regulate autophagy. Molecular and cellular biology 386 19995911
2005 Atg17 functions in cooperation with Atg1 and Atg13 in yeast autophagy. Molecular biology of the cell 284 15743910
2014 Early steps in autophagy depend on direct phosphorylation of Atg9 by the Atg1 kinase. Molecular cell 266 24440502
2023 ULK1-mediated metabolic reprogramming regulates Vps34 lipid kinase activity by its lactylation. Science advances 188 37267363
2020 SQSTM1/p62 activates NFE2L2/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity. Autophagy 181 31913745
2020 p53/microRNA-214/ULK1 axis impairs renal tubular autophagy in diabetic kidney disease. The Journal of clinical investigation 175 32804155
2020 MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis. Autophagy 174 33213267
2021 Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis. Cells 162 35011593
2019 ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97. Molecular cell 151 30979586
2016 Regulation of Autophagy By Signaling Through the Atg1/ULK1 Complex. Journal of molecular biology 142 27059781
2016 The Noncanonical Role of ULK/ATG1 in ER-to-Golgi Trafficking Is Essential for Cellular Homeostasis. Molecular cell 134 27203176
2007 ATG1, an autophagy regulator, inhibits cell growth by negatively regulating S6 kinase. EMBO reports 132 17347671
2016 Fine-tuning of ULK1 mRNA and protein levels is required for autophagy oscillation. The Journal of cell biology 121 27932573
2016 The Atg1-kinase complex tethers Atg9-vesicles to initiate autophagy. Nature communications 110 26753620
2009 Evolution of Atg1 function and regulation. Autophagy 108 19411825
2008 UNC-51/ATG1 kinase regulates axonal transport by mediating motor-cargo assembly. Genes & development 105 19056884
2021 ULK1 promotes mitophagy via phosphorylation and stabilization of BNIP3. Scientific reports 90 34654847
2019 Recruitment and Activation of the ULK1/Atg1 Kinase Complex in Selective Autophagy. Journal of molecular biology 89 31351898
2018 AMPK Inhibits ULK1-Dependent Autophagosome Formation and Lysosomal Acidification via Distinct Mechanisms. Molecular and cellular biology 87 29507183
2019 GABARAPs and LC3s have opposite roles in regulating ULK1 for autophagy induction. Autophagy 84 31208283
2016 Two Independent Pathways within Selective Autophagy Converge to Activate Atg1 Kinase at the Vacuole. Molecular cell 83 27768871
2022 NAT10 regulates neutrophil pyroptosis in sepsis via acetylating ULK1 RNA and activating STING pathway. Communications biology 81 36068299
2011 Regulation of the autophagy initiating kinase ULK1 by nutrients: roles of mTORC1 and AMPK. Cell cycle (Georgetown, Tex.) 78 21403467
2022 Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications. Acta pharmaceutica Sinica. B 76 36213540
2019 Multilayered Control of Protein Turnover by TORC1 and Atg1. Cell reports 76 31553916
2017 The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs. Nature communications 71 28924239
2020 DAPK3 inhibits gastric cancer progression via activation of ULK1-dependent autophagy. Cell death and differentiation 67 33037394
2014 Assembly and dynamics of the autophagy-initiating Atg1 complex. Proceedings of the National Academy of Sciences of the United States of America 65 25139988
2020 A Review of ULK1-Mediated Autophagy in Drug Resistance of Cancer. Cancers 64 32033142
2018 Targeted Inhibition of ULK1 Promotes Apoptosis and Suppresses Tumor Growth and Metastasis in Neuroblastoma. Molecular cancer therapeutics 64 30166400
2020 The autophagy adaptor NDP52 and the FIP200 coiled-coil allosterically activate ULK1 complex membrane recruitment. eLife 62 32773036
2020 The Autophagy-Initiating Kinase ULK1 Controls RIPK1-Mediated Cell Death. Cell reports 61 32320653
2022 Oxygen-sensitive methylation of ULK1 is required for hypoxia-induced autophagy. Nature communications 60 35246531
2019 PP2C phosphatases promote autophagy by dephosphorylation of the Atg1 complex. Proceedings of the National Academy of Sciences of the United States of America 58 30655342
2017 Canonical and noncanonical functions of ULK/Atg1. Current opinion in cell biology 58 28292700
2020 Fine-tuning of AMPK-ULK1-mTORC1 regulatory triangle is crucial for autophagy oscillation. Scientific reports 56 33082544
2010 Activation of Atg1 kinase in autophagy by regulated phosphorylation. Autophagy 55 20953146
2021 GSK3B induces autophagy by phosphorylating ULK1. Experimental & molecular medicine 54 33654220
2022 TRIM27 cooperates with STK38L to inhibit ULK1-mediated autophagy and promote tumorigenesis. The EMBO journal 53 35670107
2019 The autophagy-activating kinase ULK1 mediates clearance of free α-globin in β-thalassemia. Science translational medicine 49 31434755
2018 The deubiquitinating enzyme USP20 stabilizes ULK1 and promotes autophagy initiation. EMBO reports 48 29487085
2006 Function of the Dictyostelium discoideum Atg1 kinase during autophagy and development. Eukaryotic cell 48 17031001
2020 ULK1-ATG13 and their mitotic phospho-regulation by CDK1 connect autophagy to cell cycle. PLoS biology 47 32516310
2017 ULK1 phosphorylates Sec23A and mediates autophagy-induced inhibition of ER-to-Golgi traffic. BMC cell biology 45 28486929
2015 Chaperone-like protein p32 regulates ULK1 stability and autophagy. Cell death and differentiation 44 25909887
2022 Sulforaphane induces lipophagy through the activation of AMPK-mTOR-ULK1 pathway signaling in adipocytes. The Journal of nutritional biochemistry 41 35461903
2019 TOPK inhibits autophagy by phosphorylating ULK1 and promotes glioma resistance to TMZ. Cell death & disease 40 31378785
2013 The autophagy associated gene, ULK1, promotes tolerance to chronic and acute hypoxia. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 40 23849170
2024 Physiological functions of ULK1/2. Journal of molecular biology 39 38311233
2018 The NF-κB Factor Relish Regulates Atg1 Expression and Controls Autophagy. Cell reports 39 30463009
2020 TRAF3 promotes ROS production and pyroptosis by targeting ULK1 ubiquitination in macrophages. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 37 32275117
2016 Regulation of ULK1 Expression and Autophagy by STAT1. The Journal of biological chemistry 37 28011640
2013 ULK1 and JNK are involved in mitophagy incurred by LRRK2 G2019S expression. Protein & cell 37 27023913
2016 Human ULK1 Variation and Susceptibility to Mycobacterium tuberculosis Infection. The Journal of infectious diseases 36 27485354
2011 ULK1, mammalian target of rapamycin, and mitochondria: linking nutrient availability and autophagy. Antioxidants & redox signaling 35 21235397
2022 PERK prevents hepatic lipotoxicity by activating the p62-ULK1 axis-mediated noncanonical KEAP1-Nrf2 pathway. Redox biology 33 35091323
2021 ULK1 phosphorylation of striatin activates protein phosphatase 2A and autophagy. Cell reports 33 34592149
2015 Autophagy protein Ulk1 promotes mitochondrial apoptosis through reactive oxygen species. Free radical biology & medicine 33 26409225
2020 Function of the SNARE Ykt6 on autophagosomes requires the Dsl1 complex and the Atg1 kinase complex. EMBO reports 32 33025734
2015 Molecular interactions of the Saccharomyces cerevisiae Atg1 complex provide insights into assembly and regulatory mechanisms. Autophagy 32 25998554
2018 ULK1 Phosphorylates and Regulates Mineralocorticoid Receptor. Cell reports 31 30021155
2011 Atg1 allows second-signaled autophagic cell death in Dictyostelium. Autophagy 31 21301205
2024 Palmitoylation of ULK1 by ZDHHC13 plays a crucial role in autophagy. Nature communications 30 39169022
2023 Activation of autophagy depends on Atg1/Ulk1-mediated phosphorylation and inhibition of the Hsp90 chaperone machinery. Cell reports 30 37453059
2022 Icariin alleviates osteoarthritis through PI3K/Akt/mTOR/ULK1 signaling pathway. European journal of medical research 28 36253872
2022 Function and regulation of ULK1: From physiology to pathology. Gene 27 35905845
2020 Atg1 kinase in fission yeast is activated by Atg11-mediated dimerization and cis-autophosphorylation. eLife 27 32909946
2023 The Atg1 complex, Atg9, and Vac8 recruit PI3K complex I to the pre-autophagosomal structure. The Journal of cell biology 26 37436710
2023 An ULK1/2-PXN mechanotransduction pathway suppresses breast cancer cell migration. EMBO reports 25 37846507
2021 Multilayered regulation of autophagy by the Atg1 kinase orchestrates spatial and temporal control of autophagosome formation. Molecular cell 25 34798055
2012 Molecular cloning, characterization and expression analysis of ATG1 in the silkworm, Bombyx mori. Gene 24 23041082
2022 Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function. Autophagy 23 35104184
2020 NPM1 mutant maintains ULK1 protein stability via TRAF6-dependent ubiquitination to promote autophagic cell survival in leukemia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 33201521
2017 MicroRNA-93 Regulates Hypoxia-Induced Autophagy by Targeting ULK1. Oxidative medicine and cellular longevity 23 29109831
2024 Regulation of ULK1 by WTAP/IGF2BP3 axis enhances mitophagy and progression in epithelial ovarian cancer. Cell death & disease 22 38286802
2024 DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser56 to diminish pancreatic β cell function upon overnutrition. Science translational medicine 22 38324636
2022 TRK-fused gene (TFG) regulates ULK1 stability via TRAF3-mediated ubiquitination and protects macrophages from LPS-induced pyroptosis. Cell death & disease 21 35091545
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2023 Identification of ULK1 as a novel mitophagy-related gene in diabetic nephropathy. Frontiers in endocrinology 20 36743936
2022 ULK1 Signaling in the Liver: Autophagy Dependent and Independent Actions. Frontiers in cell and developmental biology 20 35252196
2017 Conserved and unique features of the fission yeast core Atg1 complex. Autophagy 20 28976798
2016 Beyond autophagy: New roles for ULK1 in immune signaling and interferon responses. Cytokine & growth factor reviews 20 27068414
2007 Contribution of Atg1-dependent autophagy to TOR-mediated cell growth and survival. Autophagy 20 17525525
2016 Autophagy-independent function of Atg1 for apoptosis-induced compensatory proliferation. BMC biology 19 27542914
2015 Dissecting the function of Atg1 complex in Dictyostelium autophagy reveals a connection with the pentose phosphate pathway enzyme transketolase. Open biology 19 26246495
2023 ULK1 forms distinct oligomeric states and nanoscopic structures during autophagy initiation. Science advances 18 37774021
2022 Autophagy protein ULK1 interacts with and regulates SARM1 during axonal injury. Proceedings of the National Academy of Sciences of the United States of America 18 36375051
2021 TFG binds LC3C to regulate ULK1 localization and autophagosome formation. The EMBO journal 18 33932238
2020 Yorkie Growth-Promoting Activity Is Limited by Atg1-Mediated Phosphorylation. Developmental cell 18 32032548
2023 Starvation-inactivated MTOR triggers cell migration via a ULK1-SH3PXD2A/TKS5-MMP14 pathway in ovarian carcinoma. Autophagy 17 37505094
2023 Loss of miR-144/451 alleviates β-thalassemia by stimulating ULK1-mediated autophagy of free α-globin. Blood 16 37339583
2022 Sestrin 2 Deficiency Exacerbates Noise-Induced Cochlear Injury Through Inhibiting ULK1/Parkin-Mediated Mitophagy. Antioxidants & redox signaling 16 35708118
2022 STAT3 suppresses the AMPKα/ULK1-dependent induction of autophagy in glioblastoma cells. Journal of cellular and molecular medicine 15 35670018
2014 Starvation-response may not involve Atg1-dependent autophagy induction in non-unikont parasites. Scientific reports 15 25059978
2023 The deubiquitinase Leon/USP5 interacts with Atg1/ULK1 and antagonizes autophagy. Cell death & disease 14 37607937