scholarly journals Exploitation of the Host Ubiquitin System: Means by Legionella pneumophila

2021 ◽  
Vol 12 ◽  
Author(s):  
Jingjing Luo ◽  
Lidong Wang ◽  
Lei Song ◽  
Zhao-Qing Luo
Keyword(s):  
Legionella Pneumophila ◽  
Cell Biology ◽  
Bacterial Virulence ◽  
Intracellular Pathogen ◽  
Infectious Agents ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Effective Strategies ◽  
Ubiquitin System ◽  
Common Target

Ubiquitination is a commonly used post-translational modification (PTM) in eukaryotic cells, which regulates a wide variety of cellular processes, such as differentiation, apoptosis, cell cycle, and immunity. Because of its essential role in immunity, the ubiquitin network is a common target of infectious agents, which have evolved various effective strategies to hijack and co-opt ubiquitin signaling for their benefit. The intracellular pathogen Legionella pneumophila represents one such example; it utilizes a large cohort of virulence factors called effectors to modulate diverse cellular processes, resulting in the formation a compartment called the Legionella-containing vacuole (LCV) that supports its replication. Many of these effectors function to re-orchestrate ubiquitin signaling with distinct biochemical activities. In this review, we highlight recent progress in the mechanism of action of L. pneumophila effectors involved in ubiquitination and discuss their roles in bacterial virulence and host cell biology.

scholarly journals Pathogens and polymers: Microbe–host interactions illuminate the cytoskeleton

2011 ◽  
Vol 195 (1) ◽  
pp. 7-17 ◽  
Author(s):  
Cat M. Haglund ◽  
Matthew D. Welch
Keyword(s):  
Host Cell ◽  
Membrane Trafficking ◽  
Cell Biology ◽  
Cytoskeletal Proteins ◽  
Intracellular Pathogens ◽  
Regulatory Pathways ◽  
Host Interactions ◽  
Cellular Processes ◽  
Cytoskeletal Function ◽  
Common Target

Intracellular pathogens subvert the host cell cytoskeleton to promote their own survival, replication, and dissemination. Study of these microbes has led to many discoveries about host cell biology, including the identification of cytoskeletal proteins, regulatory pathways, and mechanisms of cytoskeletal function. Actin is a common target of bacterial pathogens, but recent work also highlights the use of microtubules, cytoskeletal motors, intermediate filaments, and septins. The study of pathogen interactions with the cytoskeleton has illuminated key cellular processes such as phagocytosis, macropinocytosis, membrane trafficking, motility, autophagy, and signal transduction.

scholarly journals Legionella pneumophila regulates host cell motility by targeting Phldb2 with a 14-3-3ζ-dependent protease effector

2021 ◽  
Author(s):  
Lei Song ◽  
Jingjing Luo ◽  
Dan Huang ◽  
Yunhao Tan ◽  
Yao Liu ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Host Cell ◽  
Legionella Pneumophila ◽  
Protease Activity ◽  
Regulatory Protein ◽  
Bacterial Pathogen ◽  
Ph Domain ◽  
Cellular Processes ◽  
Common Target

The cytoskeleton network of eukaryotic cells is essential for diverse cellular processes, including vesicle trafficking, cell motility and immunity, thus is a common target for bacterial virulence factors. A number of effectors from the bacterial pathogen Legionella pneumophila have been shown to modulate the function of host actin cytoskeleton to construct the Legionella-containing vacuole (LCV) permissive for its intracellular replication. In this study, we identified the Dot/Icm effector Lem8 (Lpg1290) as a protease that interferes with host motility. We show that the protease activity of Lem8 is catalyzed by a Cys-His-Asp motif known to be associated with diverse biochemical activities. Intriguingly, we found that Lem8 interacts with the host regulatory protein 14-3-3ζ, which activates its protease activity. Furthermore, Lem8 undergoes self-cleavage in a process that requires 14-3-3ζ. We identified the PH domain-containing protein Phldb2 involved in cell migration as a target of Lem8 and demonstrate that Lem8 plays a role in the inhibition of host cell migration. Our results reveal a novel mechanism of inhibiting host cell motility by L. pneumophila for its virulence.

scholarly journals Reconstructing and Analysing The Genome of The Last Eukaryote Common Ancestor to Better Understand the Transition from FECA to LECA

2019 ◽  
Author(s):  
David Newman ◽  
Fiona J. Whelan ◽  
Matthew Moore ◽  
Martin Rusilowicz ◽  
James O. McInerney
Keyword(s):  
Cell Biology ◽  
Common Ancestor ◽  
Transition Period ◽  
Gene Families ◽  
Post Translational Modification ◽  
Kegg Database ◽  
Cellular Processes ◽  
Eukaryote Evolution ◽  
Genetic Information Processing ◽  
Eukaryotic Genomes

AbstractIt is still a matter of debate whether the First Eukaryote Common Ancestor (FECA) arose from the merger of an archaeal host with an alphaproteobacterium, or was a proto-eukaryote with significant eukaryotic characteristics way before endosymbiosis occurred. The Last Eukaryote Common Ancestor (LECA) as its descendant is thought to be an entity that possessed functional and cellular complexity comparable to modern organisms. The precise nature and physiology of both of these organisms has been a long-standing, unanswered question in evolutionary and cell biology. Recently, a much broader diversity of eukaryotic genomes has become available and this means we can reconstruct early eukaryote evolution with a greater deal of precision. Here, we reconstruct a hypothetical genome for LECA from modern eukaryote genomes. The constituent genes were mapped onto 454 pathways from the KEGG database covering cellular, genetic, and metabolic processes across six model species to provide functional insights into it’s capabilities. We reconstruct a LECA that was a facultatively anaerobic, single-celled organism, similar to a modern Protist possessing complex predatory and sexual behaviour. We go on to examine how much of these capabilities arose along the FECA-to-LECA transition period. We see a at least 1,554 genes gained by FECA during this evolutionary period with extensive remodelling of pathways relating to lipid metabolism, cellular processes, genetic information processing, protein processing, and signalling. We extracted the BRITE classifications for the genes from the KEGG database, which arose during the transition from FECA-to-LECA and examine the types of genes that saw the most gains and what novel classifications were introduced. Two-thirds of our reconstructed LECA genome appears to be prokaryote in origin and the remaining third consists of genes with functional classifications that originate from prokaryote homologs in our LECA genome. Signal transduction and Post Translational Modification elements stand out as the primary novel classes of genes developed during this period. These results suggest that largely the eukaryote common ancestors achieved the defining characteristics of modern eukaryotes by primarily expanding on prokaryote biology and gene families.

scholarly journals The interactome of Cryptococcus neoformans Rmt5 reveals multiple regulatory points in fungal cell biology and pathogenesis

2022 ◽  
Author(s):  
Murat C Kalem ◽  
Harini Subbiah ◽  
Shichen Shen ◽  
Runpu Chen ◽  
Luke Terry ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Cell Biology ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Arginine Methylation ◽  
Chromosome 9 ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Carbon Dioxide Atmosphere

Protein arginine methylation is a key post-translational modification in eukaryotes that modulates core cellular processes, including translation, morphology, transcription, and RNA fate. However, this has not been explored in Cryptococcus neoformans, a human-pathogenic basidiomycetous encapsulated fungus. We characterized the five protein arginine methyltransferases in C. neoformans and highlight Rmt5 as critical regulator of cryptococcal morphology and virulence. An rmt5∆ mutant was defective in thermotolerance, had a remodeled cell wall, and exhibited enhanced growth in an elevated carbon dioxide atmosphere and in chemically induced hypoxia. We revealed that Rmt5 interacts with post-transcriptional gene regulators, such as RNA-binding proteins and translation factors. Further investigation of the rmt5∆ mutant showed that Rmt5 is critical for the homeostasis of eIF2α and its phosphorylation state following 3-amino-1,2,4-triazole-induced ribosome stalling. RNA sequencing of one rmt5∆ clone revealed stable chromosome 9 aneuploidy that was ameliorated by complementation but did not impact the rmt5∆ phenotype. As a result of these diverse interactions and functions, loss of RMT5 enhanced phagocytosis by murine macrophages and attenuated disease progression in mice. Taken together, our findings link arginine methylation to critical cryptococcal cellular processes that impact pathogenesis, including post-transcriptional gene regulation by RNA- binding proteins.

scholarly journals How Influenza A Virus NS1 Deals with the Ubiquitin System to Evade Innate Immunity

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2309
Author(s):  
Laurie-Anne Lamotte ◽  
Lionel Tafforeau
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Influenza A Virus ◽  
Virulence Factors ◽  
Influenza A ◽  
Innate Immune ◽  
Structural Protein ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Ubiquitin System

Ubiquitination is a post-translational modification regulating critical cellular processes such as protein degradation, trafficking and signaling pathways, including activation of the innate immune response. Therefore, viruses, and particularly influenza A virus (IAV), have evolved different mechanisms to counteract this system to perform proper infection. Among IAV proteins, the non-structural protein NS1 is shown to be one of the main virulence factors involved in these viral hijackings. NS1 is notably able to inhibit the host’s antiviral response through the perturbation of ubiquitination in different ways, as discussed in this review.

scholarly journals Rab1-AMPylation by Legionella DrrA is allosterically activated by Rab1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiqing Du ◽  
Marie-Kristin von Wrisberg ◽  
Burak Gulen ◽  
Matthias Stahl ◽  
Christian Pett ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Adenosine Monophosphate ◽  
Vesicular Trafficking ◽  
Bacterial Protein ◽  
Post Translational Modification ◽  
Allosteric Control ◽  
Rab Protein ◽  
Biochemical Characterisation ◽  
A Site ◽  
Insight Into

AbstractLegionella pneumophila infects eukaryotic cells by forming a replicative organelle – the Legionella containing vacuole. During this process, the bacterial protein DrrA/SidM is secreted and manipulates the activity and post-translational modification (PTM) states of the vesicular trafficking regulator Rab1. As a result, Rab1 is modified with an adenosine monophosphate (AMP), and this process is referred to as AMPylation. Here, we use a chemical approach to stabilise low-affinity Rab:DrrA complexes in a site-specific manner to gain insight into the molecular basis of the interaction between the Rab protein and the AMPylation domain of DrrA. The crystal structure of the Rab:DrrA complex reveals a previously unknown non-conventional Rab-binding site (NC-RBS). Biochemical characterisation demonstrates allosteric stimulation of the AMPylation activity of DrrA via Rab binding to the NC-RBS. We speculate that allosteric control of DrrA could in principle prevent random and potentially cytotoxic AMPylation in the host, thereby perhaps ensuring efficient infection by Legionella.

Semisynthetic triazoles as an approach in the discovery of Novel Lead Compounds

2021 ◽  
Vol 25 ◽  
Author(s):  
Pedro Alves Bezerra Morais ◽  
Carla Santana Francisco ◽  
Heberth de Paula ◽  
Rayssa Ribeiro ◽  
Mariana Alves Eloy ◽  
...  
Keyword(s):  
Natural Products ◽  
Medicinal Chemistry ◽  
Chemical Space ◽  
Biological Activities ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Modern Drug ◽  
New Chemical Entities ◽  
Almost All ◽  
The 19Th Century

: Historically, the medicinal chemistry is concerned with the approach of organic chemistry to new drug synthesis. Considering the fruitful collections of new molecular entities, the dedicated efforts for medicinal chemistry are rewarding. Planning and search of new and applicable pharmacologic therapies involve the altruistic nature of the scientists. Since the 19th century, notoriously the application of isolated and characterized plant-derived compounds in modern drug discovery and in various stages of clinical development highlight its viability and significance. Natural products influence a broad range of biological processes, covering transcription, translation, and post-translational modification and being effective modulators of almost all basic cellular processes. The research of new chemical entities through “click chemistry” continuously opens up a map for the remarkable exploration of chemical space in towards leading natural products optimization by structure-activity relationship. Finally, here in this review, we expect to gather a broad knowledge involving triazolic natural products derivatives, synthetic routes, structures, and their biological activities.

scholarly journals The split protein phosphatase system

2018 ◽  
Vol 475 (23) ◽  
pp. 3707-3723 ◽  
Author(s):  
Anne Bertolotti
Keyword(s):  
Protein Phosphatase ◽  
Catalytic Subunit ◽  
Regulatory Subunit ◽  
Post Translational Modification ◽  
Antagonistic Action ◽  
Cellular Processes ◽  
Depth Study ◽  
Split Protein ◽  
Phosphatase System ◽  
Physiological Substrates

Reversible phosphorylation of proteins is a post-translational modification that regulates all aspect of life through the antagonistic action of kinases and phosphatases. Protein kinases are well characterized, but protein phosphatases have been relatively neglected. Protein phosphatase 1 (PP1) catalyzes the dephosphorylation of a major fraction of phospho-serines and phospho-threonines in cells and thereby controls a broad range of cellular processes. In this review, I will discuss how phosphatases were discovered, how the view that they were unselective emerged and how recent findings have revealed their exquisite selectivity. Unlike kinases, PP1 phosphatases are obligatory heteromers composed of a catalytic subunit bound to one (or two) non-catalytic subunit(s). Based on an in-depth study of two holophosphatases, I propose the following: selective dephosphorylation depends on the assembly of two components, the catalytic subunit and the non-catalytic subunit, which serves as a high-affinity substrate receptor. Because functional complementation of the two modules is required to produce a selective holophosphatase, one can consider that they are split enzymes. The non-catalytic subunit was often referred to as a regulatory subunit, but it is, in fact, an essential component of the holoenzyme. In this model, a phosphatase and its array of mostly orphan substrate receptors constitute the split protein phosphatase system. The set of potentially generalizable principles outlined in this review may facilitate the study of these poorly understood enzymes and the identification of their physiological substrates.

Functional analysis of the SUMOylation pathway in Drosophila

2008 ◽  
Vol 36 (5) ◽  
pp. 868-873 ◽  
Author(s):  
Ana Talamillo ◽  
Jonatan Sánchez ◽  
Rosa Barrio
Keyword(s):  
Functional Analysis ◽  
Fine Tuning ◽  
Model Systems ◽  
Post Translational Modification ◽  
Reversible Process ◽  
Cellular Processes ◽  
Tuning Mechanism ◽  
Sumo Conjugation

SUMOylation, a reversible process used as a ‘fine-tuning’ mechanism to regulate the role of multiple proteins, is conserved throughout evolution. This post-translational modification affects several cellular processes by the modulation of subcellular localization, activity or stability of a variety of substrates. A growing number of proteins have been identified as targets for SUMOylation, although, for many of them, the role of SUMO conjugation on their function is unknown. The use of model systems might facilitate the study of SUMOylation implications in vivo. In the present paper, we have compiled what is known about SUMOylation in Drosophila melanogaster, where the use of genetics provides new insights on SUMOylation's biological roles.

scholarly journals Structural Insights into Protein Regulation by Phosphorylation and Substrate Recognition of Protein Kinases/Phosphatases

Life ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 957
Author(s):  
Seung-Hyeon Seok
Keyword(s):  
Protein Phosphorylation ◽  
Protein Kinases ◽  
Protein Phosphatases ◽  
Substrate Recognition ◽  
Protein Structures ◽  
Phosphate Group ◽  
Amino Acid Side Chain ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Structural Insights

Protein phosphorylation is one of the most widely observed and important post-translational modification (PTM) processes. Protein phosphorylation is regulated by protein kinases, each of which covalently attaches a phosphate group to an amino acid side chain on a serine (Ser), threonine (Thr), or tyrosine (Tyr) residue of a protein, and by protein phosphatases, each of which, conversely, removes a phosphate group from a phosphoprotein. These reversible enzyme activities provide a regulatory mechanism by activating or deactivating many diverse functions of proteins in various cellular processes. In this review, their structures and substrate recognition are described and summarized, focusing on Ser/Thr protein kinases and protein Ser/Thr phosphatases, and the regulation of protein structures by phosphorylation. The studies reviewed here and the resulting information could contribute to further structural, biochemical, and combined studies on the mechanisms of protein phosphorylation and to drug discovery approaches targeting protein kinases or protein phosphatases.

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