ULK1 phosphorylation of striatin activates protein phosphatase 2A and autophagy

Hu, Zehan; Sankar, Devanarayanan Siva; Vu, Bich; Leytens, Alexandre; Vionnet, Christine; Wu, Wenxian; Stumpe, Michael; Martínez-Martínez, Esther; Stork, Björn; Dengjel, Jörn

doi:10.1016/j.celrep.2021.109762

Cited by 27 publications

(21 citation statements)

References 81 publications

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“…To further discriminate direct from indirect effects, we performed whole proteome on bead in vitro kinase assays (OBIKA) comparing the immobilized proteome of snf1 as cells growing exponentially in 5% Glucose in the presence of ATP analog, incubated with purified wild-type Snf1 to that incubated with a kinase-inactive Snf1 T210A mutant (Fig. 3A; n=5 biological replicates) (Hu et al ., 2021).…”

Section: Resultsmentioning

confidence: 99%

“…To dissect the mechanisms by which Snf1 impinges on TORC1 signaling, we decided to perform a set of stable isotope-labeling by amino acids in cell culture (SILAC)-based quantitative phosphoproteomic experiments, similarly as recently described (Hu et al, 2021). For in vivo analyses, snf1 as cells were grown in three different SILAC media supporting the comparison of three experimental conditions (Fig.…”

Section: Global Phosphoproteomics Identifies Potential Snf1 Targets W...mentioning

confidence: 99%

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Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation

Caligaris

Nicastro

et al. 2022

Preprint

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The AMP-activated protein kinase (AMPK) and the target of rapamycin complex 1 (TORC1) are central kinase modules of two opposing signaling pathways that control eukaryotic cell growth and metabolism in response to the availability of energy and nutrients. Accordingly, energy depletion activates AMPK to inhibit growth, while nutrients and high energy levels activate TORC1 to promote growth. Both in mammals and lower eukaryotes such as yeast, the AMPK and TORC1 pathways are wired to each other at different levels, which ensures homeostatic control of growth and metabolism. In this context, a previous study (Hughes Hallet et. al, 2015) reported that AMPK in yeast, i.e. Snf1, plays a role in short-term downregulation of TORC1 activity upon acute glucose starvation, but the underlying mechanism has remained elusive. Using a combination of unbiased mass spectrometry (MS)-based phosphoproteomics, genetic, biochemical, and physiological experiments, we show here that Snf1 contributes to glucose starvation-induced short-term TORC1 inactivation primarily through the TORC1-regulatory protein Pib2. Our data, therefore, extend the function of Pib2 to a hub that integrates both glucose and, as reported earlier, glutamine signals to control TORC1. We further demonstrate that Snf1 phosphorylates the TORC1 effector kinase Sch9 within its N-terminal region and thereby antagonizes the phosphorylation of a C-terminal TORC1-target residue within Sch9 itself that is critical for its activity. The consequences of Snf1-mediated phosphorylation of Pib2 and Sch9 are physiologically additive and sufficient to explain the role of Snf1 in short-term inhibition of TORC1 in acutely glucose-starved cells.

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Section: Resultsmentioning

confidence: 99%

Section: Global Phosphoproteomics Identifies Potential Snf1 Targets W...mentioning

confidence: 99%

Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation

Caligaris

Nicastro

et al. 2022

Preprint

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“… Function The substrate protein Modified site Positive regulation/ negative regulation Modification enzyme Ref. Phosphorylation ULK1 Ser317, Ser777, Ser555, Thr574, Ser637, Ser467 Activate AMPK 12 , 103 , 106 Phosphorylation ULK1 Ser757/758, Ser638, Ser467 Inhibit mTOR 103 , 104 Phosphorylation mTOR Ser2481 Inhibit ULK1 107 Phosphorylation S6k1 Thr389 Inhibit ULK1 107 Phosphorylation Raptor Ser863, Ser855, Ser859, Ser792 Inhibit ULK1 107 Phosphorylation ULK1 Ser317, Ser555 Activate MAPK15 108 , 109 Phosphorylation ULK1 Ser405, Ser415 Activate GSK3 β 110 Phosphorylation ULK1 Ser423, Ser317/555/777 Inhibit PKC α 111 , 112 Phosphorylation ULK1 Ser555, Ser757 Inhibit WNK1 113 , 114 Phosphorylation ULK1 / Activate PP2A 115 Deubiquitination …”

Section: The Molecular Basis Underlying the Regulation Mechanism Of Ulk1mentioning

confidence: 99%

“…Through phosphorylation proteomic analysis, combined with relevant experimental data, studies found that ULK1 can directly phosphorylate and promote the regulation of PP2A subunit striatum. Activated PP2A enhances autophagy through positive feedback regulation, promotes protein transport, and degrades proteins 115 . Beside the above phosphorylation regulation, there are many other proteins that regulate the phosphorylation of ULK1 ( Table 2 ), and contribute to the functions of ULK1.…”

Section: The Molecular Basis Underlying the Regulation Mechanism Of Ulk1mentioning

confidence: 99%

Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications

Zou

Liao

Zhen

et al. 2022

Acta Pharmaceutica Sinica B

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“…In some cases, Wt cultures were treated for 24h with IBA, CLX (each 10 μM) or Fo5176 elicitor (250 ug/ml) for 24h or exposed to Fo699 for 24h by addition of 10 7 conidia/ml. Total microsomes were prepared and trypsin digest was processed by using the FASP protocol overnight (Wiśniewski et al, 2009); phoshopeptides were enriched by TiO2 affinity beads (Hu et al, 2021). The tip flow-through was desalted by STAGE tips for non-phosphopeptide analysis.…”

Section: Protein Phosphorylation Analyses By Lc-ms/msmentioning

confidence: 99%

A phospho-switch provided by LRR receptor-like kinase, ALK1/QSK1/KIN7, prioritizes ABCG36/PEN3/PDR8 transport toward defense

Aryal

Xia

et al. 2022

Preprint

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Based on its proposed substrate preferences, the ABC transporter, ABCG36/PDR8/PEN3, from the model plant Arabidopsis stands at the cross-road between growth and defence. Recently, ABCG36 was shown to export a few indolic compounds, including the auxin precursor, indole-3-butyric acid (IBA), and to be implicated in the export of the major phytoalexin of Arabidopsis, camalexin, although clear-cut proof of camalexin transport activity is still lacking.Here we provide strong evidence that ABCG36 catalyses the direct, ATP-dependent export of camalexin over the plasma membrane, however, most likely in functional interplay with non-camalexin transporting ABCG isoforms. We identify the leucin-rich repeat receptor-like kinase, Auxin-induced LRR Kinase1 (ALK1/KIN7/QSK1), as a functional kinase to physically interact with and phosphorylate ABCG36. ABCG36 phosphorylation by ALK1 represses unilaterally IBA but not camalexin export leading to a prioritization of ABCG transport toward defense. As a consequence, phospho-dead mutants of ABCG36, like alk1 and abcg36 alleles, are hypersensitive toward infection with the root pathogen, F. oxysporum, caused by elevated fungal progression.Our findings indicate a novel, direct regulatory circuit between a receptor kinase and an ABC transporter determining transporter substrate specificity. It appears that growth and defense balance decisions in plants are performed on the transporter level by means of a reversible phospho-switch.

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ULK1 phosphorylation of striatin activates protein phosphatase 2A and autophagy

Abstract: Highlights d ULK1 regulates autophagosome expansion, maturation, and lysosomal fusion d ULK1 regulates an elaborate protein phosphatase network d ULK1 and striatin are linked by a regulatory feedback mechanism d Phosphorylation of striatin by ULK1 promotes functional autophagy

Cited by 27 publications

References 81 publications

Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation

Snf1/AMPK fine-tunes TORC1 signaling in response to glucose starvation

Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications

A phospho-switch provided by LRR receptor-like kinase, ALK1/QSK1/KIN7, prioritizes ABCG36/PEN3/PDR8 transport toward defense

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