Coupling Conjugation and Deconjugation Activities to Achieve Cellular Ubiquitin Dynamics

Nielsen, Casey P.; MacGurn, Jason A.

doi:10.1016/j.tibs.2020.01.008

Cited by 16 publications

(15 citation statements)

References 108 publications

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“…The function and activity of almost every cellular protein can be modulated by posttranslational modifications (PTMs) [ 1 ]. In particular, ubiquitination has emerged as one of the most conserved eukaryotic PTMs from yeast to human [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

The Giant HECT E3 Ubiquitin Ligase HERC1 Is Aberrantly Expressed in Myeloid Related Disorders and It Is a Novel BCR-ABL1 Binding Partner

Ali

Panuzzo

Calabrese

et al. 2021

Cancers

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HERC E3 subfamily members are parts of the E3 ubiquitin ligases and key players for a wide range of cellular functions. Though the involvement of the Ubiquitin Proteasome System in blood disorders has been broadly studied, so far the role of large HERCs in this context remains unexplored. In the present study we examined the expression of the large HECT E3 Ubiquitin Ligase, HERC1, in blood disorders. Our findings revealed that HERC1 gene expression was severely downregulated both in acute and in chronic myelogenous leukemia at diagnosis, while it is restored after complete remission achievement. Instead, in Philadelphia the negative myeloproliferative neoplasm HERC1 level was peculiarly controlled, being very low in Primary Myelofibrosis and significantly upregulated in those Essential Thrombocytemia specimens harboring the mutation in the calreticulin gene. Remarkably, in CML cells HERC1 mRNA level was associated with the BCR-ABL1 kinase activity and the HERC1 protein physically interacted with BCR-ABL1. Furthermore, we found that HERC1 was directly tyrosine phosphorylated by the ABL kinase. Overall and for the first time, we provide original evidence on the potential tumor-suppressing or -promoting properties, depending on the context, of HERC1 in myeloid related blood disorders.

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Section: Introductionmentioning

confidence: 99%

The Giant HECT E3 Ubiquitin Ligase HERC1 Is Aberrantly Expressed in Myeloid Related Disorders and It Is a Novel BCR-ABL1 Binding Partner

Ali

Panuzzo

Calabrese

et al. 2021

Cancers

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“…Recently it became clear that the coupling of Ub conjugating and deconjugating machineries is a common principle contributing to the regulation of complex signaling networks [ 91 ]. Ub ligases and DUBs regulate the status of protein ubiquitylation, which is crucial for essential cellular processes such as cell cycle progression, DNA repair, signal transduction, protein quality control and differentiation [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

The COP9 Signalosome: A Multi-DUB Complex

et al. 2020

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The COP9 signalosome (CSN) is a signaling platform controlling the cellular ubiquitylation status. It determines the activity and remodeling of ~700 cullin-RING ubiquitin ligases (CRLs), which control more than 20% of all ubiquitylation events in cells and thereby influence virtually any cellular pathway. In addition, it is associated with deubiquitylating enzymes (DUBs) protecting CRLs from autoubiquitylation and rescuing ubiquitylated proteins from degradation. The coordination of ubiquitylation and deubiquitylation by the CSN is presumably important for fine-tuning the precise formation of defined ubiquitin chains. Considering its intrinsic DUB activity specific for deneddylation of CRLs and belonging to the JAMM family as well as its associated DUBs, the CSN represents a multi-DUB complex. Two CSN-associated DUBs, the ubiquitin-specific protease 15 (USP15) and USP48 are regulators in the NF-κB signaling pathway. USP15 protects CRL1β-TrCP responsible for IκBα ubiquitylation, whereas USP48 stabilizes the nuclear pool of the NF-κB transcription factor RelA upon TNF stimulation by counteracting CRL2SOCS1. Moreover, the CSN controls the neddylation status of cells by its intrinsic DUB activity and by destabilizing the associated deneddylation enzyme 1 (DEN1). Thus, the CSN is a master regulator at the intersection between ubiquitylation and neddylation.

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“…In addition to interacting with allosteric regulators, DUBs also frequently associate with ubiquitin E3 ligases in cells [ 134 ]. This coupling of opposing enzymatic activities has emerged as a functionally important feature that can regulate ubiquitin signaling in diverse and complex ways [ 135 ]. DUB-E3 interactions are used for mutual ubiquitin-dependent regulation (e.g., to control each other’s stability, see above) or for editing ubiquitin chain architecture on particular substrates (as shown for the hybrid DUB/E3 enzyme A20 and CYLD-ITCH complexes during inflammatory signaling [ 136 , 137 ]).…”

Section: Regulatory Principles Impinging On Dubsmentioning

confidence: 99%

Deubiquitylases in developmental ubiquitin signaling and congenital diseases

2020

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Metazoan development from a one-cell zygote to a fully formed organism requires complex cellular differentiation and communication pathways. To coordinate these processes, embryos frequently encode signaling information with the small protein modifier ubiquitin, which is typically attached to lysine residues within substrates. During ubiquitin signaling, a three-step enzymatic cascade modifies specific substrates with topologically unique ubiquitin modifications, which mediate changes in the substrate’s stability, activity, localization, or interacting proteins. Ubiquitin signaling is critically regulated by deubiquitylases (DUBs), a class of ~100 human enzymes that oppose the conjugation of ubiquitin. DUBs control many essential cellular functions and various aspects of human physiology and development. Recent genetic studies have identified mutations in several DUBs that cause developmental disorders. Here we review principles controlling DUB activity and substrate recruitment that allow these enzymes to regulate ubiquitin signaling during development. We summarize key mechanisms of how DUBs control embryonic and postnatal differentiation processes, highlight developmental disorders that are caused by mutations in particular DUB members, and describe our current understanding of how these mutations disrupt development. Finally, we discuss how emerging tools from human disease genetics will enable the identification and study of novel congenital disease-causing DUBs.

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Coupling Conjugation and Deconjugation Activities to Achieve Cellular Ubiquitin Dynamics

Cited by 16 publications

References 108 publications

The Giant HECT E3 Ubiquitin Ligase HERC1 Is Aberrantly Expressed in Myeloid Related Disorders and It Is a Novel BCR-ABL1 Binding Partner

The Giant HECT E3 Ubiquitin Ligase HERC1 Is Aberrantly Expressed in Myeloid Related Disorders and It Is a Novel BCR-ABL1 Binding Partner

The COP9 Signalosome: A Multi-DUB Complex

Deubiquitylases in developmental ubiquitin signaling and congenital diseases

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