Ubiquitin hydrolase UCH-L1 destabilizes mTOR complex 1 by antagonizing DDB1-CUL4-mediated ubiquitination of raptor

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

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates processes including mRNA translation, proliferation, and survival. By assembling with different cofactors, mTOR forms two complexes with distinct biological functions. Raptor-bound mTOR (mTORC1) governs cap-dependent mRNA translation, whereas mTOR, rictor, and mSin1 (mTORC2) activate the survival and proliferative kinase Akt. How the balance between the competing needs for mTORC1 and-2 is controlled in normal cells and deregulated in disease is poorly understood. Here, we show that the ubiquitin hydrolase UCH-L1 regulates the balance of mTOR signaling by disrupting mTORC1. We find that UCH-L1 impairs mTORC1 activity toward S6 kinase and 4EBP1 while increasing mTORC2 activity toward Akt. These effects are directly attributable to a dramatic rearrangement in mTOR complex assembly. UCH-L1 disrupts a complex between the DDB1-CUL4 ubiquitin ligase complex and raptor and counteracts DDB1-CUL4-mediated raptor ubiquitination. These events lead to mTORC1 dissolution and a secondary increase in mTORC2. Experiments in Uchl1-deficient and transgenic mice suggest that the balance between these pathways is important for preventing neurodegeneration and the development of malignancy. These data establish UCH-L1 as a key regulator of the dichotomy between mTORC1 and mTORC2 signaling

Original languageEnglish (US)
Pages (from-to)1188-1197
Number of pages10
JournalMolecular and Cellular Biology
Volume33
Issue number6
DOIs
StatePublished - Mar 2013

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Raptors
Ubiquitination
Hydrolases
Sirolimus
Ubiquitin
Protein Biosynthesis
Ribosomal Protein S6 Kinases
Protein-Serine-Threonine Kinases
Ligases
Transgenic Mice
mechanistic target of rapamycin complex 1
Phosphotransferases
TOR complex 2

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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 Maxted; Galardy, Paul J.

In: Molecular and Cellular Biology, Vol. 33, No. 6, 03.2013, p. 1188-1197.

Research output: Contribution to journalArticle

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