Host Cell-catalyzed S-Palmitoylation Mediates Golgi Targeting of the Legionella Ubiquitin Ligase GobX

Lin, Yi‐Han; Doms, Alexandra G.; Cheng, Elaine; Kim, Byoungkwan; Evans, Timothy R.; Machner, Matthias P.

doi:10.1074/jbc.m115.637397

Cited by 59 publications

(51 citation statements)

References 62 publications

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“…Examples of the identified DUBs include SseL ( Salmonella enterica serovar Typhimurium; Rytkonen & Holden, ), Cdu1 and Cdu2 ( Chlamydia trachomatis ; Fischer et al, ; Furtado et al, ; Pruneda et al, ), and ElaD ( Escherichia coli ; Catic, Misaghi, Korbel, & Ploegh, ). L. pneumophila possesses several genes encoding E3 ubiquitin ligases, including F‐box and U‐box containing proteins (Hubber, Kubori, & Nagai, ; Lin et al, ). Recent structural analyses of L. pneumophila proteins have revealed a newly identified E3 ligase, SidC (Hsu et al, ), and bacterial DUBs that are members of the SidE effector family (Sheedlo et al, ); SidC (Luo et al, ) and the SidE DUBs (Sheedlo et al, ) are involved in phagosomal ubiquitin modification dynamics.…”

Section: Introductionmentioning

confidence: 99%

“…Examples of the identified DUBs include SseL (Salmonella enterica serovar Typhimurium; Rytkonen & Holden, 2007), Cdu1 and Cdu2 (Chlamydia trachomatis;Fischer et al, 2017;Furtado et al, 2013;Pruneda et al, 2016), and ElaD (Escherichia coli; Catic, Misaghi, Korbel, & Ploegh, 2007). L. pneumophila possesses several genes encoding E3 ubiquitin ligases, including F-box and U-box containing proteins (Hubber, Kubori, & Nagai, 2013;Lin et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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LotA, a Legionella deubiquitinase, has dual catalytic activity and contributes to intracellular growth

Kubori

Kitao

Ando

et al. 2018

Cellular Microbiology

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The intracellular bacterial pathogen, Legionella pneumophila, establishes the replicative niche as a result of the actions of a large array of effector proteins delivered via the Legionella Type 4 secretion system. Many effector proteins are expected to be involved in biogenesis and regulation of the Legionella-containing vacuole (LCV) that is highly decorated with ubiquitin. Here, we identified a Legionella deubiquitinase, designated LotA, by carrying out a genome analysis to find proteins resembling the eukaryotic ovarian tumour superfamily of cysteine proteases. LotA exhibits a dual ability to cleave ubiquitin chains that is dependent on 2 distinctive catalytic cysteine residues in the eukaryotic ovarian tumour domains. One cysteine dominantly contributes to the removal of ubiquitin from the LCVs by its polyubiquitin cleavage activity. The other specifically cleaves conjugated Lys6-linked ubiquitin. After delivered by the Type 4 secretion system, LotA localises on the LCVs via its PI(3)P-binding domain. The lipid-binding ability of LotA is crucial for ubiquitin removal from the vacuoles. We further analysed the functional interaction of the protein with the recently reported noncanonical ubiquitin ligases of L. pneumophila, revealing that the effector proteins are involved in coordinated regulation that contributes to bacterial growth in the host cells.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

LotA, a Legionella deubiquitinase, has dual catalytic activity and contributes to intracellular growth

Kubori

Kitao

Ando

et al. 2018

Cellular Microbiology

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“…Salmonella enterica type III secreted effectors SspH2 and Sse1 localize to the plasma membrane of the infected cell, and that localization is dependent on the S-palmitoylation of a cysteine residue in their N-terminal regions (13). GobX is a type IV secreted effector of Legionella pneumophila that also requires host cell palmitoylation of a cysteine residue for its specific localization (14). L. pneumophila has a second effector protein that is palmitoylated, LpdA, a virulence factor with phospholipase D activity (15).…”

Section: Discussionmentioning

confidence: 99%

Brucella Hijacks Host-Mediated Palmitoylation To Stabilize and Localize PrpA to the Plasma Membrane

et al. 2018

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are a group of pathogenic intracellular bacteria with the ability to modulate the host response, both at the individual cell level and systemically. One of the hallmarks of the virulence process is the capacity of the bacteria to downregulate the adaptive and acquired host immune response through a plethora of virulence factors that directly impact several key signaling cascades. PrpA is one of those virulence factors that alters, via its polyclonal B-cell activity, the humoral and cellular immune responses of the host, ultimately favoring the establishment of a chronic infection. Even though PrpA affects B cells, it directly targets macrophages, triggering a response that ultimately affects B lymphocytes. In the present article we report that PrpA is S-palmitoylated in two N-terminal cysteine residues by the host cell and that this modification is necessary for its biological activity. Our results demonstrate that S-palmitoylation promotes PrpA migration to the host cell plasma membrane and stabilizes the protein during infection. These findings add a new mechanism exploited by this highly evolved pathogen to modulate the host immune response.

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“…Finally, there are examples in bacteria of secreted virulence factors that are palmitoylated by the host cell, such as effector proteins in Salmonella enterica and Legionella pneumophila , which are targeted to the plasma membrane and Golgi where they mediate their effects (Hicks et al , 2011, Lin et al , 2015, Schroeder et al , 2015). Palmitoylation is required for the cell surface expression and sensitivity of the receptor which binds Bacillus anthracis anthrax toxin (Abrami et al , 2006).…”

Section: Discussionmentioning

confidence: 99%

Dynamic proteinS-palmitoylation mediates parasite life cycle progression and diverse mechanisms of virulence

Brown

Sharma

Engman

2017

Critical Reviews in Biochemistry and Molecular Biology

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Eukaryotic parasites possess complex life cycles and utilize an assortment of molecular mechanisms to overcome physical barriers, suppress and/or bypass the host immune response, including invading host cells where they can replicate in a protected intracellular niche. Protein S-palmitoylation is a dynamic post-translational modification in which the fatty acid palmitate is covalently linked to cysteine residues on proteins by the enzyme palmitoyl acyltransferase (PAT), and can be removed by lysosomal palmitoyl-protein thioesterase (PPT) or cytosolic acyl-protein thioesterase (APT). In addition to anchoring proteins to intracellular membranes, functions of dynamic palmitoylation include – targeting proteins to specific intracellular compartments via trafficking pathways, regulating the cycling of proteins between membranes, modulating protein function, and regulating protein stability. Recent studies in the eukaryotic parasites—Plasmodium falciparum, Toxoplasma gondii, Trypanosoma brucei, Cryptococcus neoformans, and Giardia lamblia—have identified large families of PATs and palmitoylated proteins. Many palmitoylated proteins are important for diverse aspects of pathogenesis, including differentiation into infective life cycle stages, biogenesis and tethering of secretory organelles, assembling the machinery powering motility, and targeting virulence factors to the plasma membrane. This review aims to summarize our current knowledge of palmitoylation in eukaryotic parasites, highlighting five exemplary mechanisms of parasite virulence dependent on palmitoylation.

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Host Cell-catalyzed S-Palmitoylation Mediates Golgi Targeting of the Legionella Ubiquitin Ligase GobX

Cited by 59 publications

References 62 publications

LotA, a Legionella deubiquitinase, has dual catalytic activity and contributes to intracellular growth

LotA, a Legionella deubiquitinase, has dual catalytic activity and contributes to intracellular growth

Brucella Hijacks Host-Mediated Palmitoylation To Stabilize and Localize PrpA to the Plasma Membrane

Dynamic proteinS-palmitoylation mediates parasite life cycle progression and diverse mechanisms of virulence

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