26 research outputs found
Aromatic amino acids at the surface of InlB are essential for host cell invasion by Listeria monocytogenes
No full textMachner MP, Frese S, Schubert WD, et al. Aromatic amino acids at the surface of InlB are essential for host cell invasion by Listeria monocytogenes. Mol Microbiol. 2003;48(6):1525-1536
Editorial: Biology and Pathogenesis of Legionella
No full textLegionella pneumophila was first isolated as the causative agent of a deadly infectious pneumonia at a convention of the American Legion forty years ago. Since then, Legionnaires’ disease continues to be a significant public health concern. Today, our understanding of the Legionella genus, comprising environmental bacteria and opportunistic human pathogens, has dramatically increased. The study of how pathogenic Legionella interact with host cells, both protozoan and mammalian, has not only taught us about host-pathogen interactions but has revealed novel and unexpected insights into human cell biology and immunology. The capacity of pathogenic Legionella to commandeer cellular processes such as eukaryotic vesicular trafficking to establish an ER-like replicative niche, reflects the exquisite ability of this pathogen to manipulate eukaryotic cell biology in order to replicate in an intracellular compartment. This requires the specific and targeted action of a cohort of translocated bacterial effector proteins. In addition, we have learnt much about cell autonomous innate immune sensing of intracellular bacteria through the inability of L. pneumophila to avoid intracellular mammalian defense mechanisms. Now, in the age of large-scale comparative “omics”, it is clear that different Legionella species utilize different cohorts of effectors to replicate inside eukaryotic cells. While we understand some of the strategies employed by L. pneumophila and L. longbeachae to replicate within eukaryotic cells, there is still much to learn about many aspects of the Legionella life cycle. This Research Topic highlights the latest findings regarding the biology of Legionella species, their interactions with eukaryotic host cells, and how the application of various technologies has increased our understanding of this important pathogen
Targeting of Host Rab GTPase Function by the Intravacuolar Pathogen Legionella pneumophila
No full textSummaryThe intracellular pathogen Legionella pneumophila replicates in a vacuole that recruits material from the host cell endoplasmic reticulum (ER). Biogenesis of this unique vacuole depends on the bacterial Dot/Icm type IV secretion system that translocates proteins across host cell membranes. Here, we show that two translocated substrates, SidM and LidA, target host cell Rab1, a small GTPase regulating ER-to-Golgi traffic. SidM is a guanosine nucleotide exchange factor for Rab1 that recruits Rab1 to Legionella-containing vacuoles, a process that is enhanced by LidA. Expression of sidM in mammalian cells interferes with the secretory pathway and causes Golgi fragmentation. Consistent with a collaborative relationship between the two proteins, immobilized SidM and LidA synergize to promote Rab1-dependent binding of early secretory vesicles. These results indicate that proteins translocated into the host cell by the intravacuolar pathogen L. pneumophila are able to recapitulate events involved in host secretory trafficking
Exploitation of the host cell ubiquitin machinery by microbial effector proteins
No full textABSTRACT
Pathogenic bacteria are in a constant battle for survival with their host. In order to gain a competitive edge, they employ a variety of sophisticated strategies that allow them to modify conserved host cell processes in ways that favor bacterial survival and growth. Ubiquitylation, the covalent attachment of the small modifier ubiquitin to target proteins, is such a pathway. Ubiquitylation profoundly alters the fate of a myriad of cellular proteins by inducing changes in their stability or function, subcellular localization or interaction with other proteins. Given the importance of ubiquitylation in cell development, protein homeostasis and innate immunity, it is not surprising that this post-translational modification is exploited by a variety of effector proteins from microbial pathogens. Here, we highlight recent advances in our understanding of the many ways microbes take advantage of host ubiquitylation, along with some surprising deviations from the canonical theme. The lessons learned from the in-depth analyses of these host–pathogen interactions provide a fresh perspective on an ancient post-translational modification that we thought was well understood.
This article is part of a Minifocus on Ubiquitin Regulation and Function. For further reading, please see related articles: ‘Mechanisms of regulation and diversification of deubiquitylating enzyme function’ by Pawel Leznicki and Yogesh Kulathu (J. Cell Sci. 130, xxxxx-xxxx). ‘Cell scientist to watch – Mads Gyrd-Hansen' (J. Cell Sci. 130, xxxxx-xxxx).</jats:p
A novel probe for phosphatidylinositol 4-phosphate reveals multiple pools beyond the Golgi
No full textCell scientist to watch – Mads Gyrd-Hansen
No full textABSTRACT
Mads Gyrd-Hansen studied biochemistry at the University of Copenhagen and received his PhD in 2005 under the supervision of Marja Jäättelä at the Danish Cancer Society Research Centre. He then joined the laboratory of Pascal Meier at the Institute of Cancer Research in London to work on the inhibitor of apoptosis (IAP) proteins. Mads returned to Copenhagen in 2008 to the Biotech Research and Innovation Centre (BRIC) in a senior postdoctoral position with Morten Frödin, and subsequently started his own research group with a career-development fellowship from the Danish Research Councils as part of the laboratory of Niels Mailand at the Novo Nordisk Foundation Centre for Protein Research. In 2013, he joined the Ludwig Institute for Cancer Research at the University of Oxford, where he is now an associate professor and holder of a Wellcome Trust Senior Research Fellowship and a Sapere Aude starting grant from the Danish Research Councils. Mads is interested in the non-degradative functions and regulation of ubiquitylation in pro-inflammatory signalling during innate immune responses.
This article is part of a Minifocus on Ubiquitin Regulation and Function. For further reading, please see related articles: ‘Mechanisms of regulation and diversification of deubiquitylating enzyme function’ by Pawel Leznicki and Yogesh Kulathu (J. Cell Sci. 130, 1997–2006). ‘Exploitation of the host cell ubiquitin machinery by microbial effector’ proteins by Yi-Han Lin and Matthias P. Machner (J. Cell Sci. 130, 1985–1996).</jats:p
A multiplex CRISPR interference tool for virulence gene interrogation in Legionella pneumophila
No full textEllis et al. present a multiplex CRISPR interference tool for Legionella pneumophila, the intracellular pathogen responsible for Legionnaires’ disease. This valuable new tool enables precise interrogation of multiple virulence genes simultaneously during host infection
Structural characterization of a previously unrecognized group of Legionella pneumophila E3 ubiquitin ligases
No full textResumen del trabajo presentado en el 41 Congreso de la Sociedad Española de Bioquímica y Biología Molecular SEBBM, celebrado en Santander (España) del 10 al 13 de septiembre de 2018.The eukaryotic ubiquitylation machinery catalyzes the covalent attachment of the small protein modifier ubiquitin to cellular target proteins in order to alter their fate. Microbial pathogens exploit this post- translational modification process by encoding molecular mimics of E3 ubiquitin ligases eukaryotic enzymes that catalyze the final step in the ubiquitylation cascade. Here we show that the Legionella pneumophila effector protein RavN belongs to a growing class of bacterial proteins that mimic host cell E3 ligases to exploit the ubiquitylation pathway. The E3 ligase activity of RavN was located within its N- terminal region and was dependent upon interaction with a defined subset of E2 ubiquitin-conjugating enzymes. The crystal structure of the N-terminal region of RavN revealed a U-box-like motif that lacks the central alpha helix commonly found in other U-box domains of eukaryotic E3s. These structural characteristics indicate that RavN is an E3 ligase relic that has undergone significant evolutionary alteration. Substitution of residues within the predicted E2 binding interface rendered RavN inactive indicating that despite significant structural changes the mode of E2 recognition has remained conserved. Using hidden Markov model-based secondary structure analyses we identified and experimentally validated four additional L. pneumophila effectors that were not previously recognized to possess E3 ligase activity including Lpg2452/SdcB a new paralog of SidC. Our study provides strong evidence thatL. pneumophilais dedicating a considerable fraction of its effector arsenal to the manipulation of the host ubiquitylation pathway
