An expanded lexicon for the ubiquitin code

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 24(4), P. 273 - 287

Published: Oct. 25, 2022

Language: Английский

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Tutorial: best practices and considerations for mass-spectrometry-based protein biomarker discovery and validation

Nature Protocols, Journal Year: 2021, Volume and Issue: 16(8), P. 3737 - 3760

Published: July 9, 2021

Language: Английский

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The ubiquitin codes in cellular stress responses

Protein & Cell, Journal Year: 2023, Volume and Issue: 15(3), P. 157 - 190

Published: July 19, 2023

Ubiquitination/ubiquitylation, one of the most fundamental post-translational modifications, regulates almost every critical cellular process in eukaryotes. Emerging evidence has shown that essential components numerous biological processes undergo ubiquitination mammalian cells upon exposure to diverse stresses, from exogenous factors reactions, causing a dazzling variety functional consequences. Various forms ubiquitin signals generated by ubiquitylation events specific milieus, known as codes, constitute an intrinsic part myriad stress responses. These events, leading proteolytic turnover substrates or just switch functionality, initiate, regulate, supervise multiple stress-associated responses, supporting adaptation, homeostasis recovery, and survival stressed cells. In this review, we attempted summarize crucial roles response different environmental intracellular while discussing how stresses modulate system. This review also updates recent advances understanding machinery well responses discusses some important questions may warrant future investigation.

Language: Английский

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Regulation of Phosphoribosyl-Linked Serine Ubiquitination by Deubiquitinases DupA and DupB

Molecular Cell, Journal Year: 2019, Volume and Issue: 77(1), P. 164 - 179.e6

Published: Nov. 12, 2019

The family of bacterial SidE enzymes catalyzes non-canonical phosphoribosyl-linked (PR) serine ubiquitination and promotes infectivity Legionella pneumophila. Here, we describe identification two effectors that reverse PR are thus named deubiquitinases for (DUPs; DupA DupB). Structural analyses revealed ubiquitin ligases harbor a highly homologous catalytic phosphodiesterase (PDE) domain. However, unlike ligases, displays increased affinity to PR-ubiquitinated substrates, which allows cleave from substrates. Interfering with DupA-ubiquitin binding switches its activity toward SidE-type ligase. Given the high exploited catalytically inactive mutant trap identify more than 180 host proteins in Legionella-infected cells. Proteins involved endoplasmic reticulum (ER) fragmentation membrane recruitment Legionella-containing vacuoles (LCV) emerged as major targets. global map substrates provides critical insights into host-pathogen interactions during infection.

Language: Английский

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Deubiquitination of phosphoribosyl-ubiquitin conjugates by phosphodiesterase-domain–containingLegionellaeffectors

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(47), P. 23518 - 23526

Published: Nov. 5, 2019

Posttranslational protein modification by ubiquitin (Ub) is a central eukaryotic mechanism that regulates plethora of physiological processes. Recent studies unveiled an unconventional type ubiquitination mediated the SidE family Legionella pneumophila effectors, such as SdeA, catalyzes conjugation Ub to serine residue target proteins via phosphoribosyl linker (hence named PR-ubiquitination). Comparable deubiquitinases in canonical pathway, here we show 2 paralogous Lpg2154 (DupA; deubiquitinase for PR-ubiquitination) and Lpg2509 (DupB), reverse PR-ubiquitination specific removal phosphoribosyl-Ub from substrates. Both DupA DupB are fully capable rescuing Golgi fragmentation phenotype caused exogenous expression SdeA mammalian cells. We further deletion these genes results significant accumulation PR-ubiquitinated species host cells infected with In addition, have identified list targets play role modulating association Legionella-containing vacuoles. Together, our data establish complete deubiquitination cycle demonstrate intricate control has over this unusual Ub-dependent posttranslational modification.

Language: Английский

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A family of conserved bacterial virulence factors dampens interferon responses by blocking calcium signaling

Cell, Journal Year: 2022, Volume and Issue: 185(13), P. 2354 - 2369.e17

Published: May 13, 2022

Interferons (IFNs) induce an antimicrobial state, protecting tissues from infection. Many viruses inhibit IFN signaling, but whether bacterial pathogens evade responses remains unclear. Here, we demonstrate that the Shigella OspC family of type-III-secreted effectors blocks signaling independently its cell death inhibitory activity. Rather, inhibition was mediated by binding OspC1 and OspC3 to Ca2+ sensor calmodulin (CaM), blocking CaM kinase II downstream JAK/STAT signaling. The growth lacking attenuated in epithelial cells a murine model This phenotype rescued both models depletion receptors. homologs conserved additional not only bound also inhibited IFN, suggesting widespread virulence strategy. These findings reveal previously undescribed molecular mechanism critical role targeting pathogenesis.

Language: Английский

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Legionella maintains host cell ubiquitin homeostasis by effectors with unique catalytic mechanisms

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 15, 2024

Abstract The intracellular bacterial pathogen Legionella pneumophila modulates host cell functions by secreting multiple effectors with diverse biochemical activities. In particular, of the SidE family interfere protein ubiquitination in a process that involves production phosphoribosyl ubiquitin (PR-Ub). Here, we show effector LnaB converts PR-Ub into ADP-ribosylated ubiquitin, which is further processed to ADP-ribose and functional (ADP-ribosyl)hydrolase MavL, thus maintaining homeostasis infected cells. Upon being activated actin, also undergoes self-AMPylation on tyrosine residues. activity requires motif consisting Ser, His Glu (SHxxxE) present large toxins from pathogens. Thus, our study sheds light mechanisms maintains identifies enzymes capable AMPylation.

Language: Английский

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Molecular Mimicry: a Paradigm of Host-Microbe Coevolution Illustrated by Legionella

mBio, Journal Year: 2020, Volume and Issue: 11(5)

Published: Oct. 5, 2020

Through coevolution with host cells, microorganisms have acquired mechanisms to avoid the detection by surveillance system and use cell’s supplies establish themselves. Indeed, certain pathogens evolved proteins that imitate specific eukaryotic cell proteins, allowing them manipulate pathways, a phenomenon termed molecular mimicry. Bacterial “eukaryotic-like proteins” are remarkable example of They defined as strongly resemble or carry domains predominantly present in eukaryotes generally absent from prokaryotes.

Language: Английский

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Protein polyglutamylation catalyzed by the bacterial calmodulin-dependent pseudokinase SidJ

eLife, Journal Year: 2019, Volume and Issue: 8

Published: Nov. 4, 2019

Pseudokinases are considered to be the inactive counterparts of conventional protein kinases and comprise approximately 10% human mouse kinomes. Here, we report crystal structure Legionella pneumophila effector protein, SidJ, in complex with eukaryotic Ca2+-binding regulator, calmodulin (CaM). The reveals that SidJ contains a kinase-like fold domain, which retains majority characteristic kinase catalytic motifs. However, fails demonstrate activity. Instead, mass spectrometry vitro biochemical analyses modifies another SdeA, an unconventional phosphoribosyl ubiquitin ligase, by adding glutamate molecules specific residue SdeA CaM-dependent manner. Furthermore, show SidJ-mediated polyglutamylation suppresses ADP-ribosylation Our work further implies some pseudokinases may possess ATP-dependent activities other than phosphorylation.

Language: Английский

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Interplay between bacterial deubiquitinase and ubiquitin E3 ligase regulates ubiquitin dynamics on Legionella phagosomes

eLife, Journal Year: 2020, Volume and Issue: 9

Published: Nov. 2, 2020

Legionella pneumophila extensively modulates the host ubiquitin network to create Legionella-containing vacuole (LCV) for its replication. Many of virulence factors function as ligases or deubiquitinases (DUBs). Here, we identify Lem27 a DUB that displays preference diubiquitin formed by K6, K11, K48. is associated with LCV where it regulates Rab10 ubiquitination in concert SidC and SdcA, two bacterial E3 ligases. Structural analysis complex an active fragment substrate-based suicide inhibitor ubiquitin-propargylamide (PA) reveals harbors fold resembling those OTU1 subfamily Cys-His catalytic dyad recognizes via extensive hydrogen bonding at six contact sites. Our results establish functions regulate protein on L. phagosomes counteracting activity

Language: Английский

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