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Noelia López-Montero, Estel Ramos-Marquès, Cristina Risco, Francisco García-Del Portillo
Xenophagy has been studied in epithelial cells infected with Salmonella enterica serovar Typhimurium (S. Typhimurium). Distinct autophagy receptors target this pathogen to degradation after interacting with ubiquitin on the surface of cytosolic bacteria, and the phagophore- and autophagosome-associated protein MAP1LC3/LC3. Glycans exposed in damaged phagosomal membranes and diacylglycerol accumulation in the phagosomal membrane also trigger S. Typhimurium xenophagy. How these responses control intraphagosomal and cytosolic bacteria remains poorly understood...
October 2, 2016: Autophagy
Tihana Bionda, Christian Behrends
Ubiquitination plays a critical role in the activation of host immune responses to infection and serves as a signal for pathogen delivery to phagophores along the xenophagy pathway. We recently performed systematic ubiquitination site profiling of epithelial cells infected with Salmonella Typhimurium. Our findings specifically highlight components of the NFKB, membrane trafficking pathways and RHO GTPase systems as ubiquitination hubs during infection. In addition, a broad spectrum of bacterial effectors and several outer membrane proteins are ubiquitinated in infected cells...
September 2016: Autophagy
Cheryl Miller, Jean Celli
Autophagy is a conserved lysosomal recycling process, which maintains cellular homeostasis during stress and starvation conditions by degrading and recycling proteins, lipids, and carbohydrates, ultimately increasing nutrient availability in eukaryotes. An additional function of autophagy, termed xenophagy, is to detect, capture, and destroy invading microorganisms, such as viruses, bacteria, and protozoa, providing autophagy with a role in innate immunity. Many intracellular pathogens have, however, developed mechanisms to avoid xenophagy and have evolved strategies to take advantage of select autophagic processes to undergo their intracellular life cycle...
August 28, 2016: Journal of Molecular Biology
Gustav van Niekerk, Ashwin W Isaacs, Theo Nell, Anna-Mart Engelbrecht
During an infection, expansion of immune cells, assembly of antibodies, and the induction of a febrile response collectively place continual metabolic strain on the host. These considerations also provide a rationale for nutritional support in critically ill patients. Yet, results from clinical and preclinical studies indicate that aggressive nutritional support does not always benefit patients and may occasionally be detrimental. Moreover, both vertebrates and invertebrates exhibit a decrease in appetite during an infection, indicating that such sickness-associated anorexia (SAA) is evolutionarily conserved...
2016: Mediators of Inflammation
Erin M Buckingham, Keith W Jarosinski, Wallen Jackson, John E Carpenter, Charles Grose
UNLABELLED: Varicella-zoster virus (VZV) is an extremely cell-associated herpesvirus with limited egress of viral particles. The induction of autophagy in VZV-infected monolayers is easily detectable; inhibition of autophagy leads to decreased VZV glycoprotein biosynthesis and diminished viral titers. To explain how autophagic flux could exert a proviral effect on the VZV infectious cycle, we postulated that the VZV exocytosis pathway following secondary envelopment may converge with the autophagy pathway...
October 1, 2016: Journal of Virology
Ashley J Dittmar, Allison A Drozda, Ira J Blader
The urgent need to develop new antimicrobial therapies has spawned the development of repurposing screens in which well-studied drugs and other types of compounds are tested for potential off-label uses. As a proof-of-principle screen to identify compounds effective against Toxoplasma gondii, we screened a collection of 1,120 compounds for the ability to significantly reduce Toxoplasma replication. A total of 94 compounds blocked parasite replication with 50% inhibitory concentrations of <5 µM. A significant number of these compounds are established inhibitors of dopamine or estrogen signaling...
March 2016: MSphere
Bor Luen Tang
Rab GTPases' subversion by intracellular pathogens during infection has been extensively documented. Recent findings have implicated a key intracellular bacterial restriction/containment function for Rab32/38 in Salmonella species in macrophages and Listeria monocytogenes in dendritic cells. Rab32/38 aids the phagolysosome maturation, and mediates a parallel xenophagy mechanism by engaging prohibitins.
May 30, 2016: Microbes and Infection
Danielle Pilla-Moffett, Matthew F Barber, Gregory A Taylor, Jörn Coers
Cell-autonomous immunity is essential for host organisms to defend themselves against invasive microbes. In vertebrates, both the adaptive and the innate branches of the immune system operate cell-autonomous defenses as key effector mechanisms that are induced by pro-inflammatory interferons (IFNs). IFNs can activate cell-intrinsic host defenses in virtually any cell type ranging from professional phagocytes to mucosal epithelial cells. Much of this IFN-induced host resistance program is dependent on four families of IFN-inducible GTPases: the myxovirus resistance proteins, the immunity-related GTPases, the guanylate-binding proteins (GBPs), and the very large IFN-inducible GTPases...
August 28, 2016: Journal of Molecular Biology
Mireille Ouimet, Stefan Koster, Erik Sakowski, Bhama Ramkhelawon, Coen van Solingen, Scott Oldebeken, Denuja Karunakaran, Cynthia Portal-Celhay, Frederick J Sheedy, Tathagat Dutta Ray, Katharine Cecchini, Philip D Zamore, Katey J Rayner, Yves L Marcel, Jennifer A Philips, Kathryn J Moore
Mycobacterium tuberculosis (Mtb) survives in macrophages by evading delivery to the lysosome and promoting the accumulation of lipid bodies, which serve as a bacterial source of nutrients. We found that by inducing the microRNA (miRNA) miR-33 and its passenger strand miR-33*, Mtb inhibited integrated pathways involved in autophagy, lysosomal function and fatty acid oxidation to support bacterial replication. Silencing of miR-33 and miR-33* by genetic or pharmacological means promoted autophagy flux through derepression of key autophagy effectors (such as ATG5, ATG12, LC3B and LAMP1) and AMPK-dependent activation of the transcription factors FOXO3 and TFEB, which enhanced lipid catabolism and Mtb xenophagy...
June 2016: Nature Immunology
Pallavi Chandra, Dhiraj Kumar
Induction of autophagy has been reported as a potential means to eliminate intracellular pathogens. Corroborating that, many studies report inhibition of autophagy as a survival strategy of bacterial pathogens. Incidentally, autophagy at the basal level is critical for survival of host cells including macrophages. We asked how a bacterial pathogen could inhibit autophagy for its survival if the inhibition resulted in cell death. In a recent study we show distinct regulation of autophagy in Mycobacterium tuberculosis (Mtb)-infected macrophages where Mtb-containing- and nonMtb-containing autophagosomes show different fates in terms of maturation...
2016: Autophagy
Gabriel Muciño, Susana Castro-Obregón, Rogelio Hernandez-Pando, Gabriel Del Rio
The emergence of complex diseases is promoting a change from one-target to multitarget drugs and peptides are ideal molecules to fulfill this polypharmacologic role. Here we review current status in the design of polypharmacological peptides aimed to treat complex diseases, focusing on tuberculosis. In this sense, combining multiple activities in single molecules is a two-sided sword, as both positive and negative side effects might arise. These polypharmacologic compounds may be directed to regulate autophagy, a catabolic process that enables cells to eliminate intracellular microbes (xenophagy), such as Mycobacterium tuberculosis (MBT)...
April 2016: IUBMB Life
Xuefeng Li, Sisi He, Xikun Zhou, Yan Ye, Shirui Tan, Shuang Zhang, Rongpeng Li, Min Yu, Michael C Jundt, Alec Hidebrand, Yongsheng Wang, Guoping Li, Canhua Huang, Min Wu
Extracellular bacteria, such as Pseudomonas aeruginosa and Klebsiella pneumoniae, have been reported to induce autophagy; however, the role and machinery of infection-induced autophagy remain elusive. We show that the pleiotropic Src kinase Lyn mediates phagocytosis and autophagosome maturation in alveolar macrophages (AM), which facilitates eventual bacterial eradication. We report that Lyn is required for bacterial infection-induced recruitment of autophagic components to pathogen-containing phagosomes. When we blocked autophagy with 3-methyladenine (3-MA) or by depleting Lyn, we observed less phagocytosis and subsequent bacterial clearance by AM...
January 2016: PLoS Pathogens
David A Tumbarello, Paul T Manna, Mark Allen, Mark Bycroft, Susan D Arden, John Kendrick-Jones, Folma Buss
Autophagy plays a key role during Salmonella infection, by eliminating these pathogens following escape into the cytosol. In this process, selective autophagy receptors, including the myosin VI adaptor proteins optineurin and NDP52, have been shown to recognize cytosolic pathogens. Here, we demonstrate that myosin VI and TAX1BP1 are recruited to ubiquitylated Salmonella and play a key role in xenophagy. The absence of TAX1BP1 causes an accumulation of ubiquitin-positive Salmonella, whereas loss of myosin VI leads to an increase in ubiquitylated and LC3-positive bacteria...
October 2015: PLoS Pathogens
S Meenu, S Thiagarajan, Sudha Ramalingam, A Michael, Sankaran Ramalingam
Endometrium is one of the most commonly affected sites in genital tuberculosis. The understanding of its interaction with the tubercle bacilli is of paramount importance for studying the pathogenesis of this disease. The main objective of this work was to study the interplay between Mycobacterium tuberculosis and host endometrial epithelial cell lines (Ishikawa cell lines), and to identify the differentially expressed genes upon tuberculosis infection. To study this, suppression subtractive hybridization library was constructed using M...
April 2016: Medical Microbiology and Immunology
Elizabeth M Selleck, Robert C Orchard, Kara G Lassen, Wandy L Beatty, Ramnik J Xavier, Beth Levine, Herbert W Virgin, L David Sibley
UNLABELLED: A core set of autophagy proteins is required for gamma interferon (IFN-γ)-mediated clearance of Toxoplasma gondii in the mouse because of their control of several downstream effectors, including immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs). However, these effectors are absent (i.e., IRGs) from or nonessential (i.e., GBPs) in IFN-γ-activated human cells, raising the question of how these cells control parasite replication. Here, we define a novel role for ubiquitination and recruitment of autophagy adaptors in the strain-specific control of T...
2015: MBio
Daniel Puleston, Kanchan Phadwal, Alexander Scarth Watson, Elizabeth J Soilleux, Suganthi Chittaranjan, Svetlana Bortnik, Sharon M Gorski, Nicholas Ktistakis, Anna Katharina Simon
Autophagy is a lysosomal catabolic pathway responsible for the degradation of cytoplasmic constituents. Autophagy is primarily a survival pathway for recycling cellular material in times of nutrient starvation, and in response to hypoxia, endoplasmic reticulum stress, and other stresses, regulated through the mammalian target of rapamycin pathway. The proteasomal pathway is responsible for degradation of proteins, whereas autophagy can degrade cytoplasmic material in bulk, including whole organelles such as mitochondria (mitophagy), bacteria (xenophagy), or lipids (lipophagy)...
September 2015: Cold Spring Harbor Protocols
Carsten Krichel, Oliver H Weiergräber, Marina Pavlidou, Jeannine Mohrlüder, Melanie Schwarten, Dieter Willbold, Philipp Neudecker
Autophagy is a versatile catabolic pathway for lysosomal degradation of cytoplasmic material. While the phenomenological and molecular characteristics of autophagic non-selective (bulk) decomposition have been investigated for decades, the focus of interest is increasingly shifting towards the selective mechanisms of autophagy. Both, selective as well as bulk autophagy critically depend on ubiquitin-like modifiers belonging to the Atg8 (autophagy-related 8) protein family. During evolution, Atg8 has diversified into eight different human genes...
April 2016: Biomolecular NMR Assignments
Michael Lazarou, Danielle A Sliter, Lesley A Kane, Shireen A Sarraf, Chunxin Wang, Jonathon L Burman, Dionisia P Sideris, Adam I Fogel, Richard J Youle
Protein aggregates and damaged organelles are tagged with ubiquitin chains to trigger selective autophagy. To initiate mitophagy, the ubiquitin kinase PINK1 phosphorylates ubiquitin to activate the ubiquitin ligase parkin, which builds ubiquitin chains on mitochondrial outer membrane proteins, where they act to recruit autophagy receptors. Using genome editing to knockout five autophagy receptors in HeLa cells, here we show that two receptors previously linked to xenophagy, NDP52 and optineurin, are the primary receptors for PINK1- and parkin-mediated mitophagy...
August 20, 2015: Nature
Erik T Sakowski, Stefan Koster, Cynthia Portal Celhay, Heidi S Park, Elina Shrestha, Stefanie E Hetzenecker, Katie Maurer, Ken Cadwell, Jennifer A Philips
The success of Mycobacterium tuberculosis (Mtb) as a pathogen rests upon its ability to grow intracellularly in macrophages. Interferon-gamma (IFN-γ) is critical in host defense against Mtb and stimulates macrophage clearance of Mtb through an autophagy pathway. Here we show that the host protein ubiquilin 1 (UBQLN1) promotes IFN-γ-mediated autophagic clearance of Mtb. Ubiquilin family members have previously been shown to recognize proteins that aggregate in neurodegenerative disorders. We find that UBQLN1 can interact with Mtb surface proteins and associates with the bacilli in vitro...
July 2015: PLoS Pathogens
Nayeli Shantal Castrejón-Jiménez, Kahiry Leyva-Paredes, Juan Carlos Hernández-González, Julieta Luna-Herrera, Blanca Estela García-Pérez
Autophagy is a highly conserved catabolic process for the degradation of cytosolic components including damaged organelles, protein aggregates, and intracellular bacteria through a lysosome-dependent pathway. Autophagy can be induced in response to stress conditions. Furthermore, autophagy has been described as involved in both innate and adaptive immune responses, and several studies have shown that certain microorganisms can be eliminated by the autophagic route in a process known as xenophagy. However, several pathogens have developed different strategies to evade or exploit autophagy to ensure their survival...
June 2015: Bioscience Trends
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