The function and regulation of OTU deubiquitinases

Du, Junjie; Fu, Lin; Sui, Yingli; Zhang, Lingqiang

doi:10.1007/s11684-019-0734-4

Cited by 46 publications

(42 citation statements)

References 171 publications

(226 reference statements)

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“…Given the expansive use of the OTU DUB fold in eukaryotes and viruses to regulate key aspects of cellular biology and infection, respectively (Du et al , ), we sought to determine whether, like the CE clan ULPs (Pruneda et al , ), the family extends into bacteria as well. Through generating a sequence alignment of eukaryotic and viral OTU domains, we created a generalized sequence profile that was used to identify related sequences among bacteria.…”

Section: Resultsmentioning

confidence: 99%

“…Humans encode 16 DUBs of the OTU family with important functions in signaling pathways such as innate immunity and cell cycle regulation (Du et al , ). Some OTUs, such as OTUB1 and OTULIN, are highly specific for certain polyUb signals (K48‐ and M1‐linked chains, respectively), and these properties not only provide insight into their biological functions (proteasomal degradation and inflammatory signaling, respectively), but also prove useful for technological applications such as ubiquitin chain restriction analysis (Keusekotten et al , ; Mevissen et al , ; Du et al , ). Viruses use OTU DUBs to block innate immune activation during infection, often by cleaving both Ub and the antiviral Ub‐like modifier ISG15 (Bailey‐Elkin et al , ).…”

Section: Introductionmentioning

confidence: 99%

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Identification and characterization of diverse OTU deubiquitinases in bacteria

et al. 2020

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Manipulation of host ubiquitin signaling is becoming an increasingly apparent evolutionary strategy among bacterial and viral pathogens. By removing host ubiquitin signals, for example, invading pathogens can inactivate immune response pathways and evade detection. The ovarian tumor (OTU) family of deubiquitinases regulates diverse ubiquitin signals in humans. Viral pathogens have also extensively co‐opted the OTU fold to subvert host signaling, but the extent to which bacteria utilize the OTU fold was unknown. We have predicted and validated a set of OTU deubiquitinases encoded by several classes of pathogenic bacteria. Biochemical assays highlight the ubiquitin and polyubiquitin linkage specificities of these bacterial deubiquitinases. By determining the ubiquitin‐bound structures of two examples, we demonstrate the novel strategies that have evolved to both thread an OTU fold and recognize a ubiquitin substrate. With these new examples, we perform the first cross‐kingdom structural analysis of the OTU fold that highlights commonalities among distantly related OTU deubiquitinases.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification and characterization of diverse OTU deubiquitinases in bacteria

et al. 2020

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“…Humans encode approximately 100 DUBs, 16 of which belong to the ovarian tumor (OTU) family, which displays great variation in structure and function (Du et al, 2019 ). The subfamily of OTU DUBs mediates important signaling cascades in eukaryotic cells, such as NF-κB signaling, interferon signaling, DNA damage repair, and immunity (Mevissen et al, 2013 ; Swatek and Komander, 2016 ).…”

Section: Lot-dubsmentioning

confidence: 99%

Divergence of Legionella Effectors Reversing Conventional and Unconventional Ubiquitination

Kitao

Nagai

Kubori

2020

Front. Cell. Infect. Microbiol.

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The intracellular bacterial pathogen Legionella pneumophila employs bacteria-derived effector proteins in a variety of functions to exploit host cellular systems. The ubiquitination machinery constitutes a crucial eukaryotic system for the regulation of numerous cellular processes, and is a representative target for effector-mediated bacterial manipulation. L. pneumophila transports over 300 effector proteins into host cells through its Dot/Icm type IV secretion system. Among these, several effector proteins have been found to function as ubiquitin ligases, including unprecedented enzymes that catalyze ubiquitination through unconventional mechanisms. Recent studies have identified many L. pneumophila effector proteins that can interfere with ubiquitination. These effectors include proteins that are distantly related to the ovarian tumor protein superfamily described as deubiquitinases (DUBs), which regulate important signaling cascades in human cells. Intriguingly, L. pneumophila DUBs are not limited to enzymes that exhibit canonical DUB activity. Some L. pneumophila DUBs can catalyze the cleavage of the unconventional linkage between ubiquitin and substrates. Furthermore, novel mechanisms have been found that adversely affect the function of specific ubiquitin ligases; for instance, effector-mediated posttranslational modifications of ubiquitin ligases result in the inhibition of their activity. In the context of L. pneumophila infection, the existence of enzymes that reverse ubiquitination primarily relates to a fine tuning of biogenesis and remodeling of the Legionella-containing vacuole as a replicative niche. The complexity of the effector arrays reflects sophisticated strategies that bacteria have adopted to adapt their host environment and enable their survival in host cells. This review summarizes the current state of knowledge on the divergent mechanisms of the L. pneumophila effectors that can reverse ubiquitination, which is mediated by other effectors as well as the host ubiquitin machinery.

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“…In yeast, the OTU DUB family contains two members, Otu1 and Otu2, while in humans, there are 16 ( figure 1 and table 1 ). Crystal structures of yeast Otu1, and several human OTUs, reveal a conserved catalytic OTU domain consisting of five β-strands sandwiched between helical domains that vary in size [ 1 , 5 , 27 ]. The active site of the OTU domain contains an unusual loop not seen in other thiol-DUBs, and may lack the catalytic Asp/Asn residue, such that several human OTU DUBs are predicted to be catalytically inactive [ 3 , 5 ].…”

Section: Deubiquitinase Families In Saccharomyces Cerevisiamentioning

confidence: 99%

The structure and function of deubiquitinases: lessons from budding yeast

2020

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Protein ubiquitination is a key post-translational modification that regulates diverse cellular processes in eukaryotic cells. The specificity of ubiquitin (Ub) signalling for different bioprocesses and pathways is dictated by the large variety of mono-ubiquitination and polyubiquitination events, including many possible chain architectures. Deubiquitinases (DUBs) reverse or edit Ub signals with high sophistication and specificity, forming an integral arm of the Ub signalling machinery, thus impinging on fundamental cellular processes including DNA damage repair, gene expression, protein quality control and organellar integrity. In this review, we discuss the many layers of DUB function and regulation, with a focus on insights gained from budding yeast. Our review provides a framework to understand key aspects of DUB biology.

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The function and regulation of OTU deubiquitinases

Cited by 46 publications

References 171 publications

Identification and characterization of diverse OTU deubiquitinases in bacteria

Identification and characterization of diverse OTU deubiquitinases in bacteria

Divergence of Legionella Effectors Reversing Conventional and Unconventional Ubiquitination

The structure and function of deubiquitinases: lessons from budding yeast

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