Ubiquitin Hydrolase UCH-L1 Destabilizes mTOR Complex 1 by Antagonizing DDB1-CUL4-Mediated Ubiquitination of Raptor

Hussain, Sajjad; Feldman, Andrew L.; Das, Chittaranjan; Ziesmer, Steven C.; Ansell, Stephen M.; Galardy, Paul J.

doi:10.1128/mcb.01389-12

Cited by 72 publications

(91 citation statements)

References 39 publications

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“…We recently reported a novel function of UCH-L1 in regulating mTOR-AKT signaling. 8 High levels of enzyme drive increased assembly of mTORC2 that phosphorylates AKT S473 , a function that requires catalytic activity. UCH-L1 antagonizes the activity of a CUL4-DDB1 ubiquitin E3 ligase in ubiquitinating the mTORC1 subunit raptor, with reduced ubiquitination seen in the presence of UCH-L1 or after the depletion of DDB1.…”

Section: Discussionmentioning

confidence: 99%

“…5,8 To determine whether a similar mechanism operates in DLBCL cells, we examined the expression of UCHL1 in the cancer cell line encyclopedia (CCLE; http://www.broadinstitute.org/ccle/home) and identified a set of GCB-DLBCL cell lines with varied expression of UCHL1, the pattern of which we confirmed by immunoblotting ( Figure 6A-B). We used a set of doxycycline (Dox)-inducible shRNA constructs to determine the impact of UCH-L1 depletion in these cells.…”

Section: Uch-l1 Promotes Mtorc2 Activity Akt Phosphorylation and Cementioning

confidence: 99%

“…5,8 Cell viability was monitored using the MTS (3-(4,5 dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl)-2H-tetrazolium) assay as described. 5,8 Flow cytometry was performed and analyzed with an Accuri C6 cytometer (Accuri Cytometers Inc, Ann Arbor, MI), using BD Accuri C6 software version 1.0.264. 21.…”

Section: Introductionmentioning

confidence: 99%

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UCH-L1 is induced in germinal center B cells and identifies patients with aggressive germinal center diffuse large B-cell lymphoma

Bedekovics

Hussain

Feldman³

et al. 2016

Blood

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• The neuronal marker UCH-L1 is induced in, and specifically augments the oncogeneinduced transformation of, GCB cells.• High levels of UCHL1 identify patients with GC DLBCL with an increased risk for poor outcomes.Gene expression profiling has identified 2 major subclasses of diffuse large B-cell lymphoma (DLBCL). Cases resembling germinal center (GC) B cells (GCB-DLBCL) generally occur in younger patients, have a distinct molecular pathophysiology, and have improved outcomes compared with those similar to activated post-GC cells (activated B-cell DLBCL). We previously found that the ubiquitin hydrolase UCH-L1 is frequently overexpressed in mature B-cell malignancies and is a potent oncogene in mice. The cause for its overexpression in lymphoma, and whether it impacts the outcome of patients with DLBCL is unknown. Here, we show that UCH-L1 reflects GC lineage in lymphoma and is an oncogenic biomarker of aggressive GCB-DLBCL. We find that UCH-L1 is specifically induced in GC B cells in mice and humans, and that its expression correlates highly with the GCB subtype in DLBCL. We also find that UCH-L1 cooperates with BCL6 in a mouse model of GC B-cell lymphoma, but not with the development of multiple myeloma derived from post-GC cells. Despite the typically good outcomes of GCB-DLBCL, increased UCHL1 identifies a subgroup with early relapses independent of MYC expression, suggesting biological diversity in this subset of disease. Consistent with this, forced Uchl1 overexpression had a substantial impact on gene expression in GC B cells including pathways of cell cycle progression, cell death and proliferation, and DNA replication. These data demonstrate a novel role for UCH-L1 outside of the nervous system and suggest its potential use as a biomarker and therapeutic target in DLBCL. (Blood. 2016;127(12):1564-1574

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Section: Discussionmentioning

confidence: 99%

Section: Uch-l1 Promotes Mtorc2 Activity Akt Phosphorylation and Cementioning

confidence: 99%

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UCH-L1 is induced in germinal center B cells and identifies patients with aggressive germinal center diffuse large B-cell lymphoma

Bedekovics

Hussain

Feldman³

et al. 2016

Blood

Self Cite

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“…2). Unfolded UCHL1 also may inhibit autophagy under pathological conditions (Hussain et al, 2013; Kabuta et al, 2008a) UCHL1 closely interacts with proteins of the neuronal cytoskeleton and may regulate axonal transport and maintain axonal integrity (Liu et al, 2002; Sakurai et al, 2008). Mutations or deletion of UCHL1 results in axonal and dendritic pathology, particularly effecting motor systems (Bilguvar et al, 2013; Chen et al, 2010; Kikuchi et al, 1990).…”

Section: Ubiquitin C-terminal Hydrolase L1 (Uchl1) and The Uppmentioning

confidence: 99%

Life and death in the trash heap: The ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia

Graham

Líu

2017

Ageing Research Reviews

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The ubiquitin proteasome pathway (UPP) is essential for removing abnormal proteins and preventing accumulation of potentially toxic proteins within the neuron. UPP dysfunction occurs with normal aging and is associated with abnormal accumulation of protein aggregates within neurons in neurodegenerative diseases. Ischemia disrupts UPP function and thus may contribute to UPP dysfunction seen in the aging brain and in neurodegenerative diseases. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1), an important component of the UPP in the neuron, is covalently modified and its activity inhibited by reactive lipids produced after ischemia. As a result, degradation of toxic proteins is impaired which may exacerbate neuronal function and cell death in stroke and neurodegenerative diseases. Preserving or restoring UCHL1 activity may be an effective therapeutic strategy in stroke and neurodegenerative diseases.

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“…8c–f). Additionally, OTUD7B, but not UCH-L1, a DUB for RPTOR 24 , targeted GβL for deubiquitination (Extended Data Fig. 8g–j).…”

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confidence: 99%

TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling

Wang

Jie

Joo

et al. 2017

Nature

158

181

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The mechanistic target of rapamycin (mTOR) has a key role in the integration of various physiological stimuli to regulate several cell growth and metabolic pathways1. mTOR primarily functions as a catalytic subunit in two structurally related but functionally distinct multi-component kinase complexes, mTOR complex 1 (mTORCl) and mTORC2 (refs 1, 2). Dysregulation of mTOR signalling is associated with a variety of human diseases, including metabolic disorders and cancer1. Thus, both mTORCl and mTORC2 kinase activity is tightly controlled in cells. mTORCl is activated by both nutrients3–6 and growth factors7, whereas mTORC2 responds primarily to extracellular cues such as growth-factor-triggered activation of PI3K signalling8–10. Although both mTOR and GβL (also known as MLST8) assemble into mTORC1 and mTORC2 (refs 11–15), it remains largely unclear what drives the dynamic assembly of these two functionally distinct complexes. Here we show, in humans and mice, that the K63-linked polyubiquitination status of GβL dictates the homeostasis of mTORC2 formation and activation. Mechanistically, the TRAF2 E3 ubiquitin ligase promotes K63-linked polyubiquitination of GβL, which disrupts its interaction with the unique mTORC2 component SIN1 (refs 12–14) to favour mTORC1 formation. By contrast, the OTUD7B deubiquitinase removes polyubiquitin chains from GβL to promote GβL interaction with SIN1, facilitating mTORC2 formation in response to various growth signals. Moreover, loss of critical ubiquitination residues in GβL, by either K305R/K313R mutations or a melanoma-associated GβL(ΔW297) truncation, leads to elevated mTORC2 formation, which facilitates tumorigenesis, in part by activating AKT oncogenic signalling. In support of a physiologically pivotal role for OTUD7B in the activation of mTORC2/AKT signalling, genetic deletion of Otud7b in mice suppresses Akt activation and Kras-driven lung tumorigenesis in vivo. Collectively, our study reveals a GβL-ubiquitination-dependent switch that fine-tunes the dynamic organization and activation of the mTORC2 kinase under both physiological and pathological conditions.

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Ubiquitin Hydrolase UCH-L1 Destabilizes mTOR Complex 1 by Antagonizing DDB1-CUL4-Mediated Ubiquitination of Raptor

Cited by 72 publications

References 39 publications

UCH-L1 is induced in germinal center B cells and identifies patients with aggressive germinal center diffuse large B-cell lymphoma

UCH-L1 is induced in germinal center B cells and identifies patients with aggressive germinal center diffuse large B-cell lymphoma

Life and death in the trash heap: The ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia

TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling

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