Calcium/Calmodulin Regulates Ubiquitination of the Ubiquitin-specific Protease TRE17/USP6

Shen, Chuanlu; Ye, Ying; Robertson, Sarah E.; Lau, Ashley; Mak, Don‐On Daniel; Chou, Margaret M.

doi:10.1074/jbc.m505220200

Cited by 48 publications

(53 citation statements)

References 36 publications

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“…23 Auto-deubiquitination regulates the mono-ubiquitination of UCH-L1 and TRE17/ USP6, which is thought to contribute to the activity of these enzymes. 24,25 Further studies are required to show if USP7 deubiquitinates itself via an intra-or intermolecular reaction and whether this possibly contributes to controlling its catalytic capabilities or protein levels. Decreased USP7 levels after treatment with a catalytic inhibitor (Fig.…”

Section: Discussionmentioning

confidence: 99%

USP7 controls Chk1 protein stability by direct deubiquitination

Vega

Martín

Smits³

2014

Cell Cycle

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Chk1, an essential checkpoint kinase in the DNA damage response pathway (DDR), is tightly regulated by both ATRdependent phosphorylation and proteasome-mediated degradation. Here we identify ubiquitin hydrolase USP7 as a novel regulator of Chk1 protein stability. USP7 was shown before to regulate other DDR proteins such as p53, Hdm2 and Claspin, an adaptor protein in the ATR-Chk1 pathway required for Chk1 activation. Depletion or inhibition of USP7 leads to lower Chk1 levels. The decreased Chk1 protein after USP7 knock down cannot be rescued by simultaneously elevating Claspin levels, demonstrating that the effect of USP7 on Chk1 is independent of its known effect on Claspin. Conversely, overexpression of USP7 wild type, but not a catalytic mutant version, elevates Chk1 levels and increases the half-life of Chk1 protein. Importantly, wild type, but not catalytic mutant USP7 can deubiquitinate Chk1 in vivo and in vitro, confirming that USP7 directly regulates Chk1 protein levels. Finally we show that USP7 catalytic mutant is (mono-)ubiquitinated, which suggests auto-deubiquitination by this ubiquitin hydrolase, possibly important for its regulation.

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Section: Discussionmentioning

confidence: 99%

USP7 controls Chk1 protein stability by direct deubiquitination

Vega

Martín

Smits³

2014

Cell Cycle

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“…To our knowledge, UCH-L1 is the first example of a DUB that is monoubiquitinated in a manner dependent on its interaction with ubiquitin. At least one other DUB, TRE17, is monoubiquitinated, and its ubiquitination occurs in a calcium-dependent manner and is dependent upon its interaction with calmodulin (36). In addition to DUBs and ubiquitin-binding proteins, ubiquitin-conjugating enzymes are targets of monoubiquitination as well.…”

Section: Discussionmentioning

confidence: 99%

Reversible Monoubiquitination Regulates the Parkinson Disease-associated Ubiquitin Hydrolase UCH-L1

Meray

Lansbury

2007

Journal of Biological Chemistry

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Deubiquitinating enzymes (DUBs) are negative regulators of protein ubiquitination and play an important role in ubiquitindependent processes. Recent studies have found that diverse cellular mechanisms are employed to control the activity of DUBs. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a highly expressed neuronal DUB linked to Parkinson disease; however, little is known about its specific functions or modes of regulation. Here, we demonstrate that UCH-L1 is post-translationally modified by monoubiquitin in cells, at lysine residues near the active site. This modification restricts enzyme activity by preventing binding to ubiquitinated targets, and permanent monoubiquitination, as mimicked by a ubiquitin-UCH-L1 fusion, inhibits UCH-L1 in its capacity to increase free ubiquitin levels in cells. Interestingly, UCH-L1 catalyzes its own deubiquitination in an intramolecular manner, thereby regulating the lifetime of this modification. Our results illustrate monoubiquitination as a reversible regulatory mechanism for DUB activity involving auto-deubiquitination.Protein ubiquitination is a central regulator in numerous cellular processes, including protein degradation, cell cycle progression, and transcriptional regulation (1). The enzymatic system for conjugating ubiquitin to protein substrates is well characterized and results in conjugation of ubiquitin to the ⑀-amino group of lysine residues or in some cases to the N-terminal amino group of target proteins (2, 3). Proteins can be modified by monomeric ubiquitin (termed monoubiquitination) or by ubiquitin chains formed by conjugation of additional ubiquitin molecules to various lysines within ubiquitin (referred to as polyubiquitination). The number and conformation of appended ubiquitin molecules determine the fate of the target protein. While Lys-48-linked polyubiquitin chains typically target proteins for proteasomal degradation, monoubiquitination at one or more lysines triggers a variety of effects depending on the substrate protein, including endocytosis, gene silencing, and DNA repair (4, 5). Our understanding of the many functions associated with ubiquitination continues to grow with the identification of additional protein substrates targeted by this versatile modification.Like protein phosphorylation, ubiquitination is reversible, and deubiquitination plays an important role in regulating ubiquitin-dependent pathways. Removal of ubiquitin is accomplished by DUBs, 2 a diverse class of nearly 80 enzymes in humans, which cleave ubiquitin from proteins, peptides, or small molecules (6, 7). Although specific substrates have been identified for relatively few DUBs, the importance of this enzyme class is highlighted by recent studies which reveal tight regulation of their activity. Transcriptional regulation, proteinprotein interactions, and post-translational modifications are known to regulate DUB activity (7,8). For example, the DUB USP1 (ubiquitin-specific protease-1) is inactivated by a UV irradiation-induced auto-cleavage event, allowing for accumulat...

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“…1A, middle, outlined with dashed lines), suggesting that TRE17 can suppress the function of MARCH8. In contrast, expression of a TRE17 point mutant that lacks DUB activity (TRE17/USP2) (Shen et al, 2005) failed to suppress the effect of MARCH8. Cells co-expressing TRE17/ USP2 and MARCH8 were indistinguishable from those expressing MARCH8 alone (Fig.…”

Section: Tre17 Counteracts March-dependent Targeting Of Cie Cargo To mentioning

confidence: 96%

“…GFP-TRE17 and GFP-TRE17/USP2 are as described previously (Martinu et al, 2004;Shen et al, 2005). cDNA of USP8 was generously provided by Yihong Ye (NIDDK, Bethesda, MD).…”

Section: Antibodies and Plasmidsmentioning

confidence: 99%

TRE17/USP6 regulates ubiquitination and trafficking of cargo proteins that enter cells by clathrin-independent endocytosis

Funakoshi¹,

Chou²,

Kanaho³

et al. 2014

Journal of Cell Science

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Plasma membrane proteins that enter cells by clathrin-independent endocytosis (CIE) are sorted either to lysosomes for degradation or recycled back to the plasma membrane. Expression of some MARCH E3 ubiquitin ligases promotes trafficking of CIE cargo proteins to lysosomes by ubiquitylating the proteins. Here, we show that co-expression of the ubiquitin-specific protease TRE17/USP6 counteracts the MARCH-dependent targeting of CIE cargo proteins, but not that of transferrin receptor, to lysosomes, leading to recovery of the stability and cell surface level of the proteins. The ubiquitylation of CIE cargo proteins by MARCH8 was reversed by TRE17, suggesting that TRE17 leads to deubiquitylation of CIE cargo proteins. The effects of TRE17 were dependent on its deubiquitylating activity and expression of TRE17 alone led to a stabilization of surface major histocompatibility complex class I (MHCI) molecules, a CIE cargo, suggesting that deubiquitylation of endogenous CIE cargo proteins promotes their stability. This study demonstrates that cycles of ubiquitylation and deubiquitylation can determine whether CIE cargo proteins are degraded or recycled.

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Calcium/Calmodulin Regulates Ubiquitination of the Ubiquitin-specific Protease TRE17/USP6

Cited by 48 publications

References 36 publications

USP7 controls Chk1 protein stability by direct deubiquitination

USP7 controls Chk1 protein stability by direct deubiquitination

Reversible Monoubiquitination Regulates the Parkinson Disease-associated Ubiquitin Hydrolase UCH-L1

TRE17/USP6 regulates ubiquitination and trafficking of cargo proteins that enter cells by clathrin-independent endocytosis

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