Sde Proteins Coordinate Ubiquitin Utilization and Phosphoribosylation to Promote Establishment and Maintenance of the Legionella Replication Vacuole DOI Creative Commons
Ralph R. Isberg,

Kristin M. Kotewicz,

Mengyun Zheng

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 18, 2023

Abstract The Legionella pneumophilaSde family of translocated proteins promote host tubular endoplasmic reticulum (ER) rearrangements that are tightly linked to phosphoribosyl-ubiquitin (pR-Ub) modification Reticulon 4 (Rtn4). Sde have two additional activities unclear relevance the infection process: K63 linkage-specific deubiquitination and phosphoribosyl polyubiquitin (pR-Ub). We show here activity (DUB) stimulates ER while pR-Ub protects replication vacuole from cytosolic surveillance by autophagy. Loss DUB was lowered Rtn4, consistent with fueling production pR-Ub-Rtn4. In parallel, polyUb, in a region protein known as isoleucine patch, caused an absolute block binding autophagy adapter p62. An inability mutants modify polyUb resulted immediate p62 association, critical precursor autophagic attack. ability WT association decayed quickly after bacterial infection, predicted presence previously characterized L. pneumophila effectors inactivate remove polyUb. sum, these results accessory act stimulate protect innate immune sensing temporal fashion.

Language: Английский

An expanded lexicon for the ubiquitin code DOI Open Access
Ivan Ðikić, Brenda A. Schulman

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

Published: Oct. 25, 2022

Language: Английский

Citations

237
Ubiquitin—A structural perspective DOI
Rashmi Agrata, David Komander

Molecular Cell, Journal Year: 2025, Volume and Issue: 85(2), P. 323 - 346

Published: Jan. 1, 2025

Language: Английский

Citations

3
Non-lysine ubiquitylation: Doing things differently DOI Creative Commons
Ian R. Kelsall

Frontiers in Molecular Biosciences, Journal Year: 2022, Volume and Issue: 9

Published: Sept. 19, 2022

The post-translational modification of proteins with ubiquitin plays a central role in nearly all aspects eukaryotic biology. Historically, studies have focused on the conjugation to lysine residues substrates, but it is now clear that ubiquitylation can also occur cysteine, serine, and threonine residues, as well N-terminal amino group proteins. Paradigm-shifting reports non-proteinaceous substrates further extended reach beyond proteome include intracellular lipids sugars. Additionally, results from bacteria revealed novel ways ubiquitylate (and deubiquitylate) without need for any enzymatic components canonical cascade. Focusing mainly upon recent findings, this review aims outline current understanding non-lysine speculate molecular mechanisms physiological importance non-canonical modification.

Language: Английский

Citations

46
The Legionella pneumophila Dot/Icm type IV secretion system and its effectors DOI
Daniel C. Lockwood, Himani Amin, Tiago R. D. Costa

et al.

Microbiology, Journal Year: 2022, Volume and Issue: 168(5)

Published: May 23, 2022

To prevail in the interaction with eukaryotic hosts, many bacterial pathogens use protein secretion systems to release virulence factors at host–pathogen interface and/or deliver them directly into host cells. An outstanding example of complexity and sophistication diversity their substrates, effectors, is Defective organelle trafficking/Intracellular multiplication (Dot/Icm) Type IVB system (T4BSS) Legionella pneumophila related species. species are facultative intracellular environmental protozoa opportunistic human respiratory pathogens. The Dot/Icm T4BSS translocates an exceptionally large number more than 300 per L. strain, essential for evasion phagolysosomal degradation exploitation macrophages as replicative niches. Recent technological advancements imaging complexes have provided new insight architecture allowed us propose models transport mechanism. At same time, significant progress has been made assigning functions about a third discovering unprecedented enzymatic activities concepts subversion. In this review, we describe current knowledge workings machinery provide overview to-date characterized effectors

Language: Английский

Citations

34
Regulation of Host-Pathogen Interactions via the Ubiquitin System DOI Open Access
Rukmini Mukherjee, Ivan Ðikić

Annual Review of Microbiology, Journal Year: 2022, Volume and Issue: 76(1), P. 211 - 233

Published: Sept. 8, 2022

Ubiquitination is a posttranslational modification that regulates multitude of cellular functions. Pathogens, such as bacteria and viruses, have evolved sophisticated mechanisms evade or counteract ubiquitin-dependent host responses, even exploit the ubiquitin system to their own advantage. This largely done by numerous pathogen virulence factors encode E3 ligases deubiquitinases, which are often used weapons in pathogen–host cell interactions. Moreover, upon attack, signaling networks undergo major changes protect cell, including coordination innate immunity, remodeling organelles, reorganization cytoskeleton, reprogramming metabolic pathways restrict growth pathogen. Here we provide mechanistic insights into regulation host-pathogen interactions how it affects bacterial viral pathogenesis organization response cell.

Language: Английский

Citations

33
Ubiquitin‐targeted bacterial effectors: rule breakers of the ubiquitin system DOI
Cameron G. Roberts, Tyler G. Franklin, Jonathan N. Pruneda

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(18)

Published: Aug. 9, 2023

Language: Английский

Citations

20
Arginine ADP-Ribosylation: Chemical Synthesis of Post-Translationally Modified Ubiquitin Proteins DOI Creative Commons

Jim Voorneveld,

Max S. Kloet, Sven Wijngaarden

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(45), P. 20582 - 20589

Published: Nov. 1, 2022

We describe the development and optimization of a methodology to prepare peptides proteins modified on arginine residue with an adenosine-di-phosphate-ribosyl (ADPr) group. Our method comprises reacting ornithine containing polypeptide on-resin α-linked anomeric isothiourea N-riboside, ensuing installment phosphomonoester at 5'-hydroxyl ribosyl moiety followed by conversion into adenosine diphosphate. use this obtain four regioisomers ADP-ribosylated ubiquitin (UbADPr), each ADP-ribosyl different position within (Ub) protein (Arg42, Arg54, Arg72, Arg74) as first reported examples fully synthetic arginine-linked ADPr-modified proteins. show chemically prepared Arg-linked UbADPr be accepted processed Legionella enzymes compare entire suite in variety biochemical experiments, allowing us profile activity selectivity pneumophila ligase hydrolase enzymes.

Language: Английский

Citations

20
The Sde phosphoribosyl–linked ubiquitin transferases protect the Legionella pneumophila vacuole from degradation by the host DOI Creative Commons
Seongok Kim, Ralph R. Isberg

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(33)

Published: Aug. 7, 2023

Legionella pneumophila grows intracellularly within the membrane-bound Legionella- containing vacuole (LCV) established by proteins translocated via bacterial type IV secretion system (T4SS). The Sde family, one such group of proteins, catalyzes phosphoribosyl–ubiquitin (pR-Ub) modification target substrates. Mutational loss entire family results in small defects intracellular growth, making it difficult to identify a clear role for this posttranslational supporting lifestyle. Therefore, mutations that aggravate sde genes and caused growth were identified, providing mechanistic connection between function biogenesis. These double mutants drove formation LCVs showed disintegration 2 h contact. appeared critical blocking access membrane-disruptive early endosomal membrane material vacuole, as RNAi depletion pathway components partially restored LCV integrity. preventing host degradation was limited earliest stages infection. time could prevent disruption, however, extended deletion sidJ , which encodes protein inactivates active sites. indicate act temporally regulated guards during establishment replication niche, possibly constructing physical barrier blocks disruptive compartments steps

Language: Английский

Citations

13
Phosphoribosyl-linked serine ubiquitination of USP14 by the SidE family effectors of Legionella excludes p62 from the bacterial phagosome DOI Creative Commons

Jinli Ge,

Ying Wang, Xindi Chen

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(8), P. 112817 - 112817

Published: July 19, 2023

Xenophagy is an evolutionarily conserved host defensive mechanism to eliminate invading microorganisms through autophagic machinery. The intracellular bacterial pathogen Legionella pneumophila can avoid clearance by the xenophagy pathway via actions of multiple Dot/Icm effector proteins. Previous studies have shown that p62, adaptor protein involved in signaling, excluded from Legionella-containing vacuoles (LCVs). Such defects are attributed multifunctional SidE family effectors (SidEs) exhibit classic deubiquitinase (DUB) and phosphoribosyl ubiquitination (PR-ubiquitination) activities, yet remains elusive. In present study, we demonstrate DUB USP14 PR-ubiquitinated SidEs at serine residues, which impairs its activity interactions with p62. exclusion p62 phagosome requires ubiquitin ligase but not SidEs. These results reveal PR-ubiquitination contributes evasion xenophagic L. pneumophila.

Language: Английский

Citations

11
Sde proteins coordinate ubiquitin utilization and phosphoribosylation to establish and maintain the Legionella replication vacuole DOI Creative Commons

Kristin M. Kotewicz,

Mengyun Zhang, Seongok Kim

et al.

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

Published: Aug. 30, 2024

The Legionella pneumophila Sde family of translocated proteins promotes host tubular endoplasmic reticulum (ER) rearrangements that are tightly linked to phosphoribosyl-ubiquitin (pR-Ub) modification Reticulon 4 (Rtn4). have two additional activities unclear relevance the infection process: K63 linkage-specific deubiquitination and phosphoribosyl polyubiquitin (pR-Ub). We show here activity (DUB) stimulates ER while pR-Ub protects replication vacuole from cytosolic surveillance by autophagy. Loss DUB is lowered Rtn4, consistent with fueling production pR-Ub-Rtn4. In parallel, polyUb, in a region protein known as isoleucine patch, prevents binding autophagy adapter p62. An inability mutants modify polyUb results immediate p62 association, critical precursor autophagic attack. ability WT block association decays quickly after bacterial infection, predicted presence previously characterized L. effectors inactivate remove polyUb. sum, these accessory act stimulate protect innate immune sensing temporal fashion.

Language: Английский

Citations

4