Host Lipidation: A Mechanism for Spatial Regulation of Legionella Effectors

Ivanov, Stanimir S.; Roy, Craig R.

doi:10.1007/82_2013_344

Cited by 16 publications

(15 citation statements)

References 62 publications

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“…For example, the Salmonella effector SifA is prenylated, aiding the membrane localization of this important effector, and prenylation of several Legionella pneumophila effectors with the C-terminal CAAX motif has been demonstrated (34). Prenylation enhances the membrane affinity for most of these effectors, facilitating their specific localization during infection (34,35). Prenylation of MceA does not modify the mitochondrial outer membrane localization or its capacity to self-assemble, but it may be important to facilitate the function of MceA at this subcellular location.…”

Section: Discussionmentioning

confidence: 99%

A Farnesylated Coxiella burnetii Effector Forms a Multimeric Complex at the Mitochondrial Outer Membrane during Infection

et al. 2017

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Coxiella burnetii, the causative agent of Q fever, establishes a unique lysosome-derived intracellular niche termed the Coxiella-containing vacuole (CCV). The Dot/Icm-type IVB secretion system is essential for the biogenesis of the CCV and the intracellular replication of Coxiella. Effector proteins, translocated into the host cell through this apparatus, act to modulate host trafficking and signaling processes to facilitate CCV development. Here we investigated the role of CBU0077, a conserved Coxiella effector that had previously been observed to localize to lysosomal membranes. CBU0077 was dispensable for the intracellular replication of Coxiella in HeLa and THP-1 cells and did not appear to participate in CCV biogenesis. Intriguingly, native and epitope-tagged CBU0077 produced by Coxiella displayed specific punctate localization at host cell mitochondria. As such, we designated CBU0077 MceA (mitochondrial Coxiella effector protein A). Analysis of ectopically expressed MceA truncations revealed that the capacity to traffic to mitochondria is encoded within the first 84 amino acids of this protein. MceA is farnesylated by the host cell; however, this does not impact mitochondrial localization. Examination of mitochondria isolated from infected cells revealed that MceA is specifically integrated into the mitochondrial outer membrane and forms a complex of approximately 120 kDa. Engineering Coxiella to express either MceA tagged with 3ϫFLAG or MceA tagged with 2ϫhemagglutinin allowed us to perform immunoprecipitation experiments that showed that MceA forms a homo-oligomeric species at the mitochondrial outer membrane during infection. This research reveals that mitochondria are a bona fide target of Coxiella effectors and MceA is a complex-forming effector at the mitochondrial outer membrane during Coxiella infection.KEYWORDS Coxiella burnetii, bacterial effector, mitochondria, prenylation, hostpathogen interactions C oxiella burnetii is the causative agent of human Q fever, a zoonotic infection with a worldwide distribution. The extremely low infectious dose, the ease of aerosol dissemination, and the environmental stability of this pathogen all contribute to Coxiella being classified as a category B select agent by the U.S. Centers for Disease Control and Prevention (1, 2).During human infection, inhaled Coxiella bacteria predominantly infect alveolar macrophages, where they develop a unique intracellular replicative niche termed the Coxiella-containing vacuole (CCV). Internalized bacteria are trafficked through the endocytic pathway until they reach the acidic and hydrolytic confines of the lysosome.

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Section: Discussionmentioning

confidence: 99%

A Farnesylated Coxiella burnetii Effector Forms a Multimeric Complex at the Mitochondrial Outer Membrane during Infection

et al. 2017

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“…For example, Legionella and other bacterial pathogens can secrete effectors that mimic the substrates of host lipid transferases, which can help them target the proper host membranes after S-acylation and other lipid modifications (Ivanov and Roy, 2013). A group of cysteine protease type III effectors secreted by the plant pathogen Pseudomonas syringae , rely on their S-acylation by the host cells to be targeted to plasma membrane and activated (Dowen et al, 2009).…”

Section: S-acylationmentioning

confidence: 99%

Progress toward Understanding Protein S-acylation: Prospective in Plants

2017

Front. Plant Sci.

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S-acylation, also known as S-palmitoylation or palmitoylation, is a reversible post-translational lipid modification in which long chain fatty acid, usually the 16-carbon palmitate, covalently attaches to a cysteine residue(s) throughout the protein via a thioester bond. It is involved in an array of important biological processes during growth and development, reproduction and stress responses in plant. S-acylation is a ubiquitous mechanism in eukaryotes catalyzed by a family of enzymes called Protein S-Acyl Transferases (PATs). Since the discovery of the first PAT in yeast in 2002 research in S-acylation has accelerated in the mammalian system and followed by in plant. However, it is still a difficult field to study due to the large number of PATs and even larger number of putative S-acylated substrate proteins they modify in each genome. This is coupled with drawbacks in the techniques used to study S-acylation, leading to the slower progress in this field compared to protein phosphorylation, for example. In this review we will summarize the discoveries made so far based on knowledge learnt from the characterization of protein S-acyltransferases and the S-acylated proteins, the interaction mechanisms between PAT and its specific substrate protein(s) in yeast and mammals. Research in protein S-acylation and PATs in plants will also be covered although this area is currently less well studied in yeast and mammalian systems.

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“…An emerging theme clearly shows that not only do translocated effectors of bacterial pathogens mimic eukaryotic protein functions, but they are also modified by various eukaryotic post-translational modification machineries (Ivanov and Roy, 2013; Kim et al, 2014). Our data show for the first time that injected effectors are modified by host FIH-dependent asparaginyl hydroxylation.…”

Section: Discussionmentioning

confidence: 99%

Host FIH-Mediated Asparaginyl Hydroxylation of Translocated Legionella pneumophila Effectors

Price

Merchant

Jones

et al. 2017

Front. Cell. Infect. Microbiol.

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FIH-mediated post-translational modification through asparaginyl hydroxylation of eukaryotic proteins impacts regulation of protein-protein interaction. We have identified the FIH recognition motif in 11 Legionella pneumophila translocated effectors, YopM of Yersinia, IpaH4.5 of Shigella and an ankyrin protein of Rickettsia. Mass spectrometry analyses of the AnkB and AnkH effectors of L. pneumophila confirm their asparaginyl hydroxylation. Consistent with localization of the AnkB effector to the Legionella-containing vacuole (LCV) membrane and its modification by FIH, our data show that FIH and its two interacting proteins, Mint3 and MT1-MMP are acquired by the LCV in a Dot/Icm type IV secretion-dependent manner. Chemical inhibition or RNAi-mediated knockdown of FIH promotes LCV-lysosomes fusion, diminishes decoration of the LCV with polyubiquitinated proteins, and abolishes intra-vacuolar replication of L. pneumophila. These data show acquisition of the host FIH by a pathogen-containing vacuole and that asparaginyl-hydroxylation of translocated effectors is indispensable for their function.

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Host Lipidation: A Mechanism for Spatial Regulation of Legionella Effectors

Cited by 16 publications

References 62 publications

A Farnesylated Coxiella burnetii Effector Forms a Multimeric Complex at the Mitochondrial Outer Membrane during Infection

A Farnesylated Coxiella burnetii Effector Forms a Multimeric Complex at the Mitochondrial Outer Membrane during Infection

Progress toward Understanding Protein S-acylation: Prospective in Plants

Host FIH-Mediated Asparaginyl Hydroxylation of Translocated Legionella pneumophila Effectors

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