TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation

Fitzian, Katharina; Brückner, Anne; Brohée, Laura; Zech, R.; Antoni, Claudia; Kiontke, Stephan; Gasper, Raphael; Matos, Anna Lívia Linard; Beel, Stephanie; Wilhelm, Sabine; Gerke, Volker; Ungermann, Christian; Nellist, Mark; Raunser, Stefan; Demetriades, Constantinos; Oeckinghaus, Andrea; Kümmel, Daniel

doi:10.1016/j.molcel.2021.04.019

Cited by 28 publications

(29 citation statements)

References 83 publications

(112 reference statements)

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“…As first reported by Manning and Demetriades, starvation and growth factor or amino acid depletion moves TSC2 to the lysosome to reduce Rheb-GTP binding and suppress mTORC1, whereas Akt activation does the opposite ( Demetriades et al, 2014 ; Menon et al, 2014 ; Demetriades et al, 2016 ). In 2021, Fitzian et al (2021) reported that TSC1 is central to this translocation, binding to phosphoinositol phospholipid PI3,5P2 at the lysosomal membrane to position TSC2 for mTORC1 inhibition. Whether this or other mechanisms apply to TSC complex movement from lysosomes after Akt or ERK1/2 activation or their selective modulation by S1364 remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Given the multiplicity of signaling kinase inputs that rarely occur in isolation, their interactions and hierarchy is important to understand, yet this remains under studied. A dominant mechanism of TSC1/TSC2 regulation involves its intracellular localization to or away from the lysosomal membrane where Rheb and mTORC1 reside ( Menon et al, 2014 ; Carroll et al, 2016 ; Demetriades et al, 2016 ; Fitzian et al, 2021 ). Nutrient starvation or depletion of growth factors sends the TSC complex to lysosomes in a TSC1-dependent manner ( Fitzian et al, 2021 ) to inhibit mTORC1, whereas growth factor stimulation as by insulin stimulates mTORC1 via translocating the TSC1/2 complex away from the lysosome ( Menon et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…A dominant mechanism of TSC1/TSC2 regulation involves its intracellular localization to or away from the lysosomal membrane where Rheb and mTORC1 reside ( Menon et al, 2014 ; Carroll et al, 2016 ; Demetriades et al, 2016 ; Fitzian et al, 2021 ). Nutrient starvation or depletion of growth factors sends the TSC complex to lysosomes in a TSC1-dependent manner ( Fitzian et al, 2021 ) to inhibit mTORC1, whereas growth factor stimulation as by insulin stimulates mTORC1 via translocating the TSC1/2 complex away from the lysosome ( Menon et al, 2014 ). This translocation can be out-competed by nutrient ( Menon et al, 2014 ) or energy depletion ( Inoki et al, 2003 ; Ranek et al, 2019 ), reducing mTORC1 activity despite growth stimulation.…”

Section: Introductionmentioning

confidence: 99%

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Single serine on TSC2 exerts biased control over mTORC1 activation mediated by ERK1/2 but not Akt

et al. 2022

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Tuberous sclerosis complex-2 (TSC2) negatively regulates mammalian target of rapamycin complex 1 (mTORC1), and its activity is reduced by protein kinase B (Akt) and extracellular response kinase (ERK1/2) phosphorylation to activate mTORC1. Serine 1364 (human) on TSC2 bidirectionally modifies mTORC1 activation by pathological growth factors or hemodynamic stress but has no impact on resting activity. We now show this modification biases to ERK1/2 but not Akt-dependent TSC2-mTORC1 activation. Endothelin-1–stimulated mTORC1 requires ERK1/2 activation and is bidirectionally modified by phospho-mimetic (S1364E) or phospho-silenced (S1364A) mutations. However, mTORC1 activation by Akt-dependent stimuli (insulin or PDGF) is unaltered by S1364 modification. Thrombin stimulates both pathways, yet only the ERK1/2 component is modulated by S1364. S1364 also has negligible impact on mTORC1 regulation by energy or nutrient status. In vivo, diet-induced obesity, diabetes, and fatty liver couple to Akt activation and are also unaltered by TSC2 S1364 mutations. This contrasts to prior reports showing a marked impact of both on pathological pressure-stress. Thus, S1364 provides ERK1/2-selective mTORC1 control and a genetic means to modify pathological versus physiological mTOR stimuli.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Single serine on TSC2 exerts biased control over mTORC1 activation mediated by ERK1/2 but not Akt

et al. 2022

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“…However, the TSC complex suppresses mTORC1 also under stress (Plescher et al, 2015;Demetriades et al, 2016) and mechanisms other than G3BP-TSC2 may take over for the lysosomal tethering of the TSC complex. Findings of Fitzian et al (2021) suggest the involvement of lysosomal phospholipids as TSC1 binds PI(3,5)P2 (phosphatidylinositol-3,5-bisphosphate) in a charge dependent manner (Figure 1). Osmotic stress enhances PI(3,5)P2 levels in the lysosomal membrane (Jin et al, 2017), and it is conceivable that lysosomal tethering of the TSC complex via TSC1 becomes dominant under stress conditions.…”

Section: Crosstalk Of Lysosomes and Sgs In Tsc Complex-mtorc1 Signalingmentioning

confidence: 99%

“…A growing body of evidence shows that stress granules (SGs) constitute a nonmembranous compartment at which mTORC1 is inhibited under stress through several mechanisms (Takahara and Maeda, 2012;Thedieck et al, 2013;Wippich et al, 2013;Ramiscal et al, 2015;Lastres-Becker et al, 2016;Pla-Martin et al, 2020;Mediani et al, 2021). Whereas the molecular machinery mediating the recruitment and regulation of mTORC1 at lysosomes (Rabanal-Ruiz and Korolchuk, 2018;Condon and Sabatini, 2019;Kim and Guan, 2019) or SGs (Takahara and Maeda, 2012;Thedieck et al, 2013;Wippich et al, 2013;Mediani et al, 2021) has been investigated in much detail, recent studies shed light on the mechanisms tethering the TSC complex to lysosomes (Fitzian et al, 2021;Prentzell et al, 2021) and to SGs (Kosmas et al, 2021). In this mini-review we summarize the latest findings focusing on the interplay of the TSC complex with SGs and lysosomes.…”

Section: Introductionmentioning

confidence: 99%

The TSC Complex-mTORC1 Axis: From Lysosomes to Stress Granules and Back

Rehbein

Prentzell

Sandoval

et al. 2021

Front. Cell Dev. Biol.

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The tuberous sclerosis protein complex (TSC complex) is a key integrator of metabolic signals and cellular stress. In response to nutrient shortage and stresses, the TSC complex inhibits the mechanistic target of rapamycin complex 1 (mTORC1) at the lysosomes. mTORC1 is also inhibited by stress granules (SGs), RNA-protein assemblies that dissociate mTORC1. The mechanisms of lysosome and SG recruitment of mTORC1 are well studied. In contrast, molecular details on lysosomal recruitment of the TSC complex have emerged only recently. The TSC complex subunit 1 (TSC1) binds lysosomes via phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2]. The SG assembly factors 1 and 2 (G3BP1/2) have an unexpected lysosomal function in recruiting TSC2 when SGs are absent. In addition, high density lipoprotein binding protein (HDLBP, also named Vigilin) recruits TSC2 to SGs under stress. In this mini-review, we integrate the molecular mechanisms of lysosome and SG recruitment of the TSC complex. We discuss their interplay in the context of cell proliferation and migration in cancer and in the clinical manifestations of tuberous sclerosis complex disease (TSC) and lymphangioleiomyomatosis (LAM).

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Design of negative‐regulating proteins of Rheb/mTORC1with much‐reduced sizes of the tuberous sclerosis protein complex

2023

Protein Science

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The mTORC1 signaling pathway regulates cell growth and metabolism in a variety of organisms from yeast to human, and inhibition of the mTORC1 pathway has the prospect to treat cancer or achieve longevity. The tuberous sclerosis protein complex (TSCC) is a master negative regulator of the mTORC1 signaling pathway through hydrolyzing the GTP loaded on the small GTPase Rheb, which is a key activator of mTOR. However, the large size (~700 kDa) and complex structural organization of TSCC render it vulnerable to degradation and inactivation, thus limiting its potential application. In this work, based on thorough analysis and understanding of the structural mechanism of how the stabilization domain of TSC2 secures the association of TSC2‐GAP with Rheb and thus enhances its GAP activity, we designed two proteins, namely SSG‐MTM (short stabilization domain and GAP domain‐membrane targeting motif) and SSG‐TSC1N, which were able to function like TSCC to negatively regulate Rheb and mTORC1, but with much‐reduced sizes (~1/15 and ~ 1/9 of the size of TSCC, respectively). Biochemical and cell biological assays demonstrated that these designed proteins indeed could promote the GTPase activity of Rheb to hydrolyze GTP, inhibit the kinase activity of mTORC1, and prevent mTORC1 from down‐regulating catabolism and autophagy.

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TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation

Cited by 28 publications

References 83 publications

Single serine on TSC2 exerts biased control over mTORC1 activation mediated by ERK1/2 but not Akt

Single serine on TSC2 exerts biased control over mTORC1 activation mediated by ERK1/2 but not Akt

The TSC Complex-mTORC1 Axis: From Lysosomes to Stress Granules and Back

Design of negative‐regulating proteins of Rheb/mTORC1with much‐reduced sizes of the tuberous sclerosis protein complex

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