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Author

Nicole Lau

Other affiliations: Washington State University
Bio: Nicole Lau is an academic researcher from University of Melbourne. The author has contributed to research in topics: Effector & Vacuole. The author has an hindex of 3, co-authored 3 publications receiving 49 citations. Previous affiliations of Nicole Lau include Washington State University.

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Journal ArticleDOI
TL;DR: The structure-function analysis shows that the carboxy-terminal seven amino acids of SopF are essential for its membrane association in host cells and to promote SCV membrane stability.
Abstract: The enteric bacterial pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium), utilizes two type III secretion systems (T3SSs) to invade host cells, survive and replicate intracellularly. T3SS1 and its dedicated effector proteins are required for bacterial entry into non-phagocytic cells and establishment and trafficking of the nascent Salmonella-containing vacuole (SCV). Here we identify the first T3SS1 effector required to maintain the integrity of the nascent SCV as SopF. SopF associates with host cell membranes, either when translocated by bacteria or ectopically expressed. Recombinant SopF binds to multiple phosphoinositides in protein-lipid overlays, suggesting that it targets eukaryotic cell membranes via phospholipid interactions. In yeast, the subcellular localization of SopF is dependent on the activity of Mss4, a phosphatidylinositol 4-phosphate 5-kinase that generates PI(4,5)P2 from PI(4)P, indicating that membrane recruitment of SopF requires specific phospholipids. Ectopically expressed SopF partially colocalizes with specific phosphoinositide pools present on the plasma membrane in mammalian cells and with cytoskeletal-associated markers at the leading edge of cells. Translocated SopF concentrates on plasma membrane ruffles and around intracellular bacteria, presumably on the SCV. SopF is not required for bacterial invasion of non-phagocytic cells but is required for maintenance of the internalization vacuole membrane as infection with a S. Typhimurium ΔsopF mutant led to increased lysis of the SCV compared to wild type bacteria. Our structure-function analysis shows that the carboxy-terminal seven amino acids of SopF are essential for its membrane association in host cells and to promote SCV membrane stability. We also describe that SopF and another T3SS1 effector, SopB, act antagonistically to modulate nascent SCV membrane dynamics. In summary, our study highlights that a delicate balance of type III effector activities regulates the stability of the Salmonella internalization vacuole.

49 citations

Journal ArticleDOI
TL;DR: This study identified host proteins that contribute to the pathogen’s capacity to establish this niche and activate the Dot/Icm secretion system required for intracellular replication and demonstrated the importance of multiple protein families required for endocytic trafficking of the C. burnetii-containing vacuole to the lysosome.
Abstract: Coxiella burnetii is an intracellular pathogen that replicates in a lysosome-like vacuole through activation of a Dot/Icm-type IVB secretion system and subsequent translocation of effectors that remodel the host cell. Here a genome-wide small interfering RNA screen and reporter assay were used to identify host proteins required for Dot/Icm effector translocation. Significant, and independently validated, hits demonstrated the importance of multiple protein families required for endocytic trafficking of the C. burnetii-containing vacuole to the lysosome. Further analysis demonstrated that the degradative activity of the lysosome created by proteases, such as TPP1, which are transported to the lysosome by receptors, such as M6PR and LRP1, are critical for C. burnetii virulence. Indeed, the C. burnetii PmrA/B regulon, responsible for transcriptional up-regulation of genes encoding the Dot/Icm apparatus and a subset of effectors, induced expression of a virulence-associated transcriptome in response to degradative products of the lysosome. Luciferase reporter strains, and subsequent RNA-sequencing analysis, demonstrated that particular amino acids activate the C. burnetii PmrA/B two-component system. This study has further enhanced our understanding of C. burnetii pathogenesis, the host-pathogen interactions that contribute to bacterial virulence, and the different environmental triggers pathogens can sense to facilitate virulence.

32 citations

Journal ArticleDOI
TL;DR: The effector proteins that Legionella pneumophila and Coxiella burnetii utilize to modulate the host autophagy pathway in order to survive and replicate are explored.
Abstract: Autophagy is a fundamental and highly conserved eukaryotic process, responsible for maintaining cellular homeostasis and releasing nutrients during times of starvation. An increasingly important function of autophagy is its role in the cell autonomous immune response; a process known as xenophagy. Intracellular pathogens are engulfed by autophagosomes and targeted to lysosomes to eliminate the threat to the host cell. To counteract this, many intracellular bacterial pathogens have developed unique approaches to overcome, evade, or co-opt host autophagy to facilitate a successful infection. The intracellular bacteria Legionella pneumophila and Coxiella burnetii are able to avoid destruction by the cell, causing Legionnaires' disease and Q fever, respectively. Despite being related and employing homologous Dot/Icm type 4 secretion systems (T4SS) to translocate effector proteins into the host cell, these pathogens have developed their own unique intracellular niches. L. pneumophila evades the host endocytic pathway and instead forms an ER-derived vacuole, while C. burnetii requires delivery to mature, acidified endosomes which it remodels into a large, replicative vacuole. Throughout infection, L. pneumophila effectors act at multiple points to inhibit recognition by xenophagy receptors and disrupt host autophagy, ensuring it avoids fusion with destructive lysosomes. In contrast, C. burnetii employs its effector cohort to control autophagy, hypothesized to facilitate the delivery of nutrients and membrane to support the growing vacuole and replicating bacteria. In this review we explore the effector proteins that these two organisms utilize to modulate the host autophagy pathway in order to survive and replicate. By better understanding how these pathogens manipulate this highly conserved pathway, we can not only develop better treatments for these important human diseases, but also better understand and control autophagy in the context of human health and disease.

26 citations

Journal ArticleDOI
TL;DR: In this paper , SetDB1-deficient epidermal keratinocytes showed DNA hypomethylation at both gene loci and distinct ERVs throughout the genome, which was associated with increased expression of ERV-specific dsRNAs and induction of interferon-mediated activation of innate immune skin response.

Cited by
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TL;DR: The results highlight the importance of intestinal epithelial NAIP/NLRC4 in blocking bacterial dissemination in vivo, and explain why this constitutes a uniquely evasion-proof defense against the adapted enteropathogen S. Tm.

75 citations

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TL;DR: The molecular machinery underlying dynamic SCV growth and shrinkage is identified and the SNARE proteins SNAP25 and STX4 participate in SCV inflation by fusion with macropinosomes, indicating that host compartment size control emerges as a pathogen strategy for intracellular niche regulation.

46 citations

Journal ArticleDOI
TL;DR: In this paper, a library of 32 Salmonella enterica serovar Typhimurium (STm) strains expressing chromosomally encoded affinity-tagged effectors and quantified effector-host PPIs in macrophages and epithelial cells.

32 citations

Journal ArticleDOI
TL;DR: In this article , Hooper et al. reveal new insights into how V-ATPase V0-V1 engagement recruits the autophagy protein ATG16L1 to direct the conjugation of ATG8.
Abstract: Hooper et al. report on the role and regulation of V-ATPase in the activation of non-canonical autophagy, including LC3-associated phagocytosis. They reveal new insights into how V-ATPase V0-V1 engagement recruits the autophagy protein ATG16L1 to direct the conjugation of ATG8 to single membranes.

31 citations

Journal ArticleDOI
TL;DR: It is shown that caspase-1 is important for restricting intracellular S. Typhimurium replication and initiating IL-18 secretion in mouse I ECs but is dispensable in human IECs, highlighting the differences between mouse and human Iecs and the utility of studying transformed and untransformed cells in parallel.
Abstract: Recent studies have determined that inflammasome signaling plays an important role in driving intestinal epithelial cell (IEC) responses to bacterial infections, such as Salmonella enterica serovar Typhimurium (S. Typhimurium). There are two primary inflammasome pathways, canonical (involving caspase-1) and non-canonical (involving caspase-4 and -5 in humans and caspase-11 in mice). Prior studies identified the canonical inflammasome as the major pathway leading to interleukin-18 (IL-18) release and restriction of S. Typhimurium replication in the mouse cecum. In contrast, the human C2Bbe1 colorectal carcinoma cell line expresses little caspase-1 but instead utilizes caspase-4 to respond to S. Typhimurium infection. Intestinal enteroid culture has enabled long-term propagation of untransformed IECs from multiple species, including mouse and human. Capitalizing on this technology, we used a genetic approach to directly compare the relative importance of different inflammatory caspases in untransformed mouse and human IECs and transformed human IECs upon S. Typhimurium infection in vitro. We show that caspase-1 is important for restricting intracellular S. Typhimurium replication and initiation of IL-18 secretion in mouse IECs but is dispensable in human IECs. In contrast, restriction of intracellular S. Typhimurium and production of IL-18 is dependent on caspase-4 in both transformed and untransformed human IECs. Notably, cytosolic replication in untransformed cells from both species was less pronounced than in transformed human cells, suggesting that transformation may impact additional pathways that restrict S. Typhimurium replication. Taken together, these data highlight the differences between mouse and human IECs and the utility of studying transformed and untransformed cells in parallel.

30 citations