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Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates.

ABSTRACT: The two main routes that cells use for degrading intracellular proteins are the ubiquitin-proteasome and autophagy-lysosome pathways, which have been thought to have largely distinct clients. Here, we show that autophagy inhibition increases levels of proteasome substrates. This is largely due to p62 (also called A170/SQSTM1) accumulation after autophagy inhibition. Excess p62 inhibits the clearance of ubiquitinated proteins destined for proteasomal degradation by delaying their delivery to the proteasome's proteases. Our data show that autophagy inhibition, which was previously believed to only affect long-lived proteins, will also compromise the ubiquitin-proteasome system. This will lead to increased levels of short-lived regulatory proteins, like p53, as well as the accumulation of aggregation-prone proteins, with predicted deleterious consequences.

SUBMITTER: Korolchuk VI

PROVIDER: S-EPMC2669153 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates.

Korolchuk Viktor I VI Mansilla Alicia A Menzies Fiona M FM Rubinsztein David C DC

Molecular cell 20090201 4

The two main routes that cells use for degrading intracellular proteins are the ubiquitin-proteasome and autophagy-lysosome pathways, which have been thought to have largely distinct clients. Here, we show that autophagy inhibition increases levels of proteasome substrates. This is largely due to p62 (also called A170/SQSTM1) accumulation after autophagy inhibition. Excess p62 inhibits the clearance of ubiquitinated proteins destined for proteasomal degradation by delaying their delivery to the ...[more]

PMID: 19250912

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Project description:BackgroundUbiquitination is a post-translational modification where ubiquitin is covalently attached to lysine residues on substrate proteins to signal their degradation by the 26S proteasome or initiate other non-degradation functions such as cellular trafficking. The diversity of ubiquitin modifications can be attributed to the variable number of ubiquitin molecules attached to a lysine residue (mono- vs. poly-ubiquitin chains), the type of covalent linkages within poly-ubiquitin chains and the number of lysine residues on a substrate that are occupied by ubiquitin at any given time. The integral role ubiquitination plays in cell homeostasis is reflected by the multitude of diseases associated with impaired ubiquitin modification, rendering it the focus of extensive research initiatives and proteomic discovery studies. However, determining the functional role of distinct ubiquitin modifications directly from proteomic data remains challenging and represents a bottleneck in the process of deciphering how ubiquitination at specific substrate sites impacts cell signaling.MethodsIn this study SILAC coupled with LC-MS/MS is used to identify ubiquitinated proteins in SKOV3 ovarian cancer cells, with the implementation of a computational approach that measures relative ubiquitin occupancy at distinct modification sites upon 26S proteasome inhibition and uses that data to infer functional significance.ResultsIn addition to identifying and quantifying relative ubiquitin occupancy at distinct post-translational modification sites to distinguish degradation from non-degradation signaling, this research led to the discovery of nine ubiquitination sites in the oncoprotein HER2 that have not been previously reported in ovarian cancer. Subsequently the computational approach applied in this study was utilized to infer the functional role of individual HER2 ubiquitin-modified residues.ConclusionsIn summary, the computational method, previously described for glycosylation analysis, was used in this study for the assessment of ubiquitin stoichiometries and applied directly to proteomic data to distinguish degradation from non-degradation ubiquitin functions.

Dataset Information

Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates.

Publications

Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates.

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