The species-spanning family of LPX-motif harbouring effector proteins

Norkowski, Stefanie; Schmidt, M. Alexander; Rüter, Christian

doi:10.1111/cmi.12945

Cited by 15 publications

(21 citation statements)

References 82 publications

(171 reference statements)

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“…It should be noted that nucleomodulins, like many toxins and effectors, often have several different ligands and subcellular localizations. Thus, they can perform multiple functions, as shown for instance for effectors with ubiquitin ligase or methyltransferase activities [70,75,117]. Nucleomodulin diversity is also gradually being uncovered in plant pathogenic bacteria, as well as in protozoa and fungi.…”

Section: Discussionmentioning

confidence: 99%

“…In the nucleus, IpaH9.8 targets a splicing factor, U2AF35 (or U2AF1), suggesting that it may interfere with mRNA splicing [72][73][74] (Figure 2C). IpaH enzymes are a family of bacterial effectors characterized by a particular N-terminal leucine-rich repeat (LRR) domain, referred to as the LPX domain [75], which is involved in substrate recognition, and a C-terminal E3 ubiquitin ligase domain, named NEL (novel E3 ligase) [75][76][77]. The NEL domain has an original structure that differs from known eukaryotic models but retains the catalytic cysteine characteristic of E3, demonstrating functional mimicry.…”

Section: Nucleomodulins Triggering Ptm On Nuclear Regulatorsmentioning

confidence: 99%

“…Pathogenic Yersinia species Y. pestis, Y. pseudotuberculosis and Y. enterocolitica secrete a nucleomodulin related to IpaH and Ssph1 [75]. Yersinia outer protein M (YopM) possesses a LPX-type domain and traffic to the nucleus [80,81].…”

Section: Nucleomodulins Triggering Ptm On Nuclear Regulatorsmentioning

confidence: 99%

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Bacterial Factors Targeting the Nucleus: The Growing Family of Nucleomodulins

Bierne

Pourpre

2020

Toxins

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Pathogenic bacteria secrete a variety of proteins that manipulate host cell function by targeting components of the plasma membrane, cytosol, or organelles. In the last decade, several studies identified bacterial factors acting within the nucleus on gene expression or other nuclear processes, which has led to the emergence of a new family of effectors called “nucleomodulins”. In human and animal pathogens, Listeria monocytogenes for Gram-positive bacteria and Anaplasma phagocytophilum, Ehrlichia chaffeensis, Chlamydia trachomatis, Legionella pneumophila, Shigella flexneri, and Escherichia coli for Gram-negative bacteria, have led to pioneering discoveries. In this review, we present these paradigms and detail various mechanisms and core elements (e.g., DNA, histones, epigenetic regulators, transcription or splicing factors, signaling proteins) targeted by nucleomodulins. We particularly focus on nucleomodulins interacting with epifactors, such as LntA of Listeria and ankyrin repeat- or tandem repeat-containing effectors of Rickettsiales, and nucleomodulins from various bacterial species acting as post-translational modification enzymes. The study of bacterial nucleomodulins not only generates important knowledge about the control of host responses by microbes but also creates new tools to decipher the dynamic regulations that occur in the nucleus. This research also has potential applications in the field of biotechnology. Finally, this raises questions about the epigenetic effects of infectious diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Nucleomodulins Triggering Ptm On Nuclear Regulatorsmentioning

confidence: 99%

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Bacterial Factors Targeting the Nucleus: The Growing Family of Nucleomodulins

Bierne

Pourpre

2020

Toxins

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“…YopM is member of the leucine‐rich repeat (LRR)‐containing effector superfamily that can promote virulence by several different mechanisms 60 . The LRRs are located in the central domain of YopM, and the number of repeats can vary between 13 and 21 in different Yersinia strains.…”

Section: The Pyrin‐yersinia Effector Interactionmentioning

confidence: 99%

The pyrin inflammasome and the Yersinia effector interaction

Malik

Bliska

2020

Immunological Reviews

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Pyrin is a cytosolic pattern‐recognition receptor that normally functions as a guard to trigger capase‐1 inflammasome assembly in response to bacterial toxins and effectors that inactivate RhoA. The MEFV gene encoding human pyrin is preferentially expressed in phagocytes. Key domains in pyrin include a pyrin domain (PYD), a linker region, and a B30.2 domain. Binding of ASC to pyrin by a PYD‐PYD interaction triggers inflammasome assembly. Pyrin is held in an inactive conformation by negative regulation mechanisms to avoid premature inflammasome assembly. One mechanism of negative regulation involves phosphorylation of the linker by PRK kinase which in turn is positively regulated by active RhoA. The B30.2 domain also negatively regulates pyrin. Gain of function mutations in MEFV responsible for the autoinflammatory disease Familial Mediterranean Fever (FMF) map to exon 10 encoding the B30.2 domain. Insights into pyrin regulation have come from studies of several Yersinia effectors, which are injected into phagocytes and interact with the RhoA‐PRK‐pyrin axis during infection. Two effectors, YopE and YopT, inactivate RhoA to disrupt phagocytic signaling. To counteract an effector‐triggered immune response, a third effector, YopM, binds to and inhibits pyrin by hijacking PRK and RSK and directing linker phosphorylation. Inhibition of pyrin by YopM is required for virulence of Yersinia pestis, the agent of plague. Recent results from infection studies with human phagocytes and mice producing pyrin B30.2 FMF variants show that gain of function MEFV mutations bypass inhibition by YopM. Population genetic data suggest that MEFV mutations were selected for in individuals of Mediterranean decent during historic plague pandemics. This review discusses current concepts of pyrin regulation and its interaction with Yersinia effectors.

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“…An N-terminal reassortment hypothesis was proposed to explain the evolution of T3SEs and their signal sequences (26), and the complete conservation of signal sequences was further used to screen new T3SEs (27). Conserved motifs present in effector domains of T3SEs, e.g., EPIYA and LPX, have been discovered and used successfully for prediction of new T3SEs (28,29). Conservation was also found in the promoter regions for effector genes, and several T3SEs were successfully predicted using this feature (30,31).…”

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confidence: 99%

T3SEpp: an Integrated Prediction Pipeline for Bacterial Type III Secreted Effectors

et al. 2020

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Many Gram-negative bacteria infect hosts and cause diseases by translocating a variety of type III secreted effectors (T3SEs) into the host cell cytoplasm. However, despite a dramatic increase in the number of available whole-genome sequences, it remains challenging for accurate prediction of T3SEs. Traditional prediction models have focused on atypical sequence features buried in the N-terminal peptides of T3SEs, but unfortunately, these models have had high false-positive rates. In this research, we integrated promoter information along with characteristic protein features for signal regions, chaperone-binding domains, and effector domains for T3SE prediction. Machine learning algorithms, including deep learning, were adopted to predict the atypical features mainly buried in signal sequences of T3SEs, followed by development of a voting-based ensemble model integrating the individual prediction results. We assembled this into a unified T3SE prediction pipeline, T3SEpp, which integrated the results of individual modules, resulting in high accuracy (i.e., ∼0.94) and >1-fold reduction in the false-positive rate compared to that of state-of-the-art software tools. The T3SEpp pipeline and sequence features observed here will facilitate the accurate identification of new T3SEs, with numerous benefits for future studies on host-pathogen interactions. IMPORTANCE Type III secreted effector (T3SE) prediction remains a big computational challenge. In practical applications, current software tools often suffer problems of high false-positive rates. One of the causal factors could be the relatively unitary type of biological features used for the design and training of the models. In this research, we made a comprehensive survey on the sequence-based features of T3SEs, including signal sequences, chaperone-binding domains, effector domains, and transcription factor binding promoter sites, and assembled a unified prediction pipeline integrating multi-aspect biological features within homology-based and multiple machine learning models. To our knowledge, we have compiled the most comprehensive biological sequence feature analysis for T3SEs in this research. The T3SEpp pipeline integrating the variety of features and assembling different models showed high accuracy, which should facilitate more accurate identification of T3SEs in new and existing bacterial whole-genome sequences.

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The species-spanning family of LPX-motif harbouring effector proteins

Cited by 15 publications

References 82 publications

Bacterial Factors Targeting the Nucleus: The Growing Family of Nucleomodulins

Bacterial Factors Targeting the Nucleus: The Growing Family of Nucleomodulins

The pyrin inflammasome and the Yersinia effector interaction

T3SEpp: an Integrated Prediction Pipeline for Bacterial Type III Secreted Effectors

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