The Ubiquitination of RagA GTPase by RNF152 Negatively Regulates mTORC1 Activation

Deng, Lu; Jiang, Cong; Chen, Lei; Jin, Jiali; Wei, Jie; Zhao, Linlin; Chen, Ming‐Hui; Pan, Weijuan; Yan, Xu; Chu, Hongshang; Wang, Xinbo; Ge, Xin; Li, Dali; Liao, Lujian; Liu, Mingyao; Li, Li; Wang, Ping

doi:10.1016/j.molcel.2015.03.033

Cited by 98 publications

(115 citation statements)

References 38 publications

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“…Two independent studies demonstrated that RAGA ubiquitination promotes its binding to GATOR1, leading to inactivation of RAGA [63,64]. Deng et al [64] identified RNF152 as the E3 ubiquitin ligase that mediates ubiquitination of RAGA at lysine 142, 220, 230, and 244, while Jin et al [63] found that another E3 ubiquitin ligase, SKP2, mediates ubiquitination of RAGA at lysine 15. Each study showed that the described ubiquitination increases interaction between RAGA and GATOR1, and overexpression of a RAGA ubiquitination-deficient mutant (K142R, K220R, K230R, K244R, or K15R) reduces RAGA-GATOR1 interaction, and thus increases mTORC1 activity.…”

Section: Rnf152 and Skp2 E3 Ubiquitin Ligases For Ragamentioning

confidence: 99%

“…How are RNF152 and SKP2 regulated in response to amino acids? Deng et al [64] showed that amino acid starvation increases RNF152 interaction with RAGA and RAGA ubiquitination. However, RNF152 preferentially binds to the already inactive RAGA-GDP, suggesting that RNF152-mediated ubiquitination is not the primary mechanism of RAGA inactivation by GATOR1.…”

Section: Rnf152 and Skp2 E3 Ubiquitin Ligases For Ragamentioning

confidence: 99%

“…Jin et al proposed that SKP2-mediated RAGA ubiquitination is a negative feedback mechanism to prevent mTORC1 hyperactivation upon amino acid stimulation. Both studies showed that MEFs from RNF152-or SKP2-knockout mice have increased mTORC1 activity, presumably due to increased RAGA-GTP levels [63,64]. Curiously, both RNF152 and SKP2 knockout mice are viable [64,65] in contrast to neonatal lethality conferred by RAGA-GTP knockin [66] or SESN knockout [59] (see below).…”

Section: Rnf152 and Skp2 E3 Ubiquitin Ligases For Ragamentioning

confidence: 99%

“…Both studies showed that MEFs from RNF152-or SKP2-knockout mice have increased mTORC1 activity, presumably due to increased RAGA-GTP levels [63,64]. Curiously, both RNF152 and SKP2 knockout mice are viable [64,65] in contrast to neonatal lethality conferred by RAGA-GTP knockin [66] or SESN knockout [59] (see below). This may suggest that RNF152 and SKP2 have a small role in mTORC1 physiology, or their function may be relevant only in specific physiological contexts.…”

Section: Rnf152 and Skp2 E3 Ubiquitin Ligases For Ragamentioning

confidence: 99%

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Multiple amino acid sensing inputs to mTORC1

2015

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The evolutionarily conserved target of rapamycin complex 1 (TORC1) is a master regulator of cell growth and metabolism. In mammals, growth factors and cellular energy stimulate mTORC1 activity through inhibition of the TSC complex (TSC1-TSC2-TBC1D7), a negative regulator of mTORC1. Amino acids signal to mTORC1 independently of the TSC complex. Here, we review recently identified regulators that link amino acid sufficiency to mTORC1 activity and how mutations affecting these regulators cause human disease.

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Section: Rnf152 and Skp2 E3 Ubiquitin Ligases For Ragamentioning

confidence: 99%

Section: Rnf152 and Skp2 E3 Ubiquitin Ligases For Ragamentioning

confidence: 99%

Section: Rnf152 and Skp2 E3 Ubiquitin Ligases For Ragamentioning

confidence: 99%

Section: Rnf152 and Skp2 E3 Ubiquitin Ligases For Ragamentioning

confidence: 99%

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Multiple amino acid sensing inputs to mTORC1

2015

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“…8b,c). Because the Rag GTPases serve as a metabolic switch that can reciprocally regulate AMPK and mTORC1 pathways 51 and the GATOR complex is one of the critical regulators of this switch 52,53 , hSesn2-mediated inhibition of GATOR2 and subsequent activation of GATOR1 (refs 27-29) may be the key signalling event that affects both the AMPK and mTORC1 signalling pathways.…”

Section: Discussionmentioning

confidence: 99%

Janus-Faced Sestrin2 Controls ROS and MTOR Signalling Through Two Separate Functional Domains

Kim

et al. 2016

Free Radical Biology and Medicine

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Sestrins are stress-inducible metabolic regulators with two seemingly unrelated but physiologically important functions: reduction of reactive oxygen species (ROS) and inhibition of the mechanistic target of rapamycin complex 1 (mTORC1). How Sestrins fulfil this dual role has remained elusive so far. Here we report the crystal structure of human Sestrin2 (hSesn2), and show that hSesn2 is twofold pseudo-symmetric with two globular subdomains, which are structurally similar but functionally distinct from each other. While the N-terminal domain (Sesn-A) reduces alkylhydroperoxide radicals through its helix-turn-helix oxidoreductase motif, the C-terminal domain (Sesn-C) modified this motif to accommodate physical interaction with GATOR2 and subsequent inhibition of mTORC1. These findings clarify the molecular mechanism of how Sestrins can attenuate degenerative processes such as aging and diabetes by acting as a simultaneous inhibitor of ROS accumulation and mTORC1 activation.

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The E3 ubiquitin ligase MARCH3 controls the endothelial barrier

et al. 2016

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Cell-cell contacts coordinate the endothelial barrier function in response to external cues. To identify new mediators involved in cytokine-promoted endothelial permeability, we screened a siRNA library targeting E3 ubiquitin ligases. Here, we report that silencing of the late endosome/lysosomal membrane-associated RING-CH-3 (MARCH3) enzyme protects the endothelial barrier. Furthermore, transcriptome analysis unmasked the upregulation of the tight junction-encoding gene occludin (OCLN) in MARCH3-depleted cells. Indeed, MARCH3 silencing results in the strengthening of cell-cell contacts, as evidenced by the accumulation of junctional proteins. From a molecular standpoint, the FoxO1 forkhead transcription repressor was inactivated in the absence of MARCH3. This provides a possible molecular link between MARCH3 and the signaling pathway involved in regulating the expression of junctional proteins and barrier integrity.

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The Ubiquitination of RagA GTPase by RNF152 Negatively Regulates mTORC1 Activation

Abstract: Highlights d Amino acid signaling regulates RagA ubiquitination d RNF152 targets RagA for K63-linked ubiquitination d RagA ubiquitination by RNF152 inhibits RagA and mTORC1 activation d RagA ubiquitination promotes its binding to GATOR1

Cited by 98 publications

References 38 publications

Multiple amino acid sensing inputs to mTORC1

Multiple amino acid sensing inputs to mTORC1

Janus-Faced Sestrin2 Controls ROS and MTOR Signalling Through Two Separate Functional Domains

The E3 ubiquitin ligase MARCH3 controls the endothelial barrier

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