Autophagy and selective deployment of Atg proteins in antiviral defense
2013; 25 (1): 1-10
Mitoxosome: a mitochondrial platform for cross-talk between cellular stress and antiviral signaling
2011; 243: 215-234
Autophagy is an evolutionarily ancient process eukaryotic cells utilize to remove and recycle intracellular material in order to maintain cellular homeostasis. In metazoans, the autophagy machinery not only functions in this capacity but also has evolved to perform a diverse repertoire of intracellular transport and regulatory functions. In response to virus infections, the autophagy machinery degrades viruses, shuttles viral pathogen-associated molecular patterns to endosomes containing Toll-like receptors, facilitates viral-antigen processing for major histocompatibility complex presentation and transports antiviral proteins to viral replication sites. This is accomplished through canonical autophagy or through processes involving distinct subsets of the autophagy-related genes (Atgs). Herein, we discuss how the variable components of the autophagy machinery contribute to antiviral defense and highlight three emerging themes: first, autophagy delivers viral cytosolic components to several distinct endolysosomal compartments; second, Atg proteins act alone, as subgroups or collectively; and third, the specificity of autophagy and the autophagy machinery is achieved by recognition of triggers and selective targeting by adaptors.
View details for DOI 10.1093/intimm/dxs101
View details for Web of Science ID 000313127400001
View details for PubMedID 23042773
Autophagic control of RLR signaling
2009; 5 (5): 749-750
Evidence is accumulating that the mitochondria form an integral platform from which innate signaling takes place. Recent studies revealed that the mitochondria are shaping the innate response to intracellular pathogens, and mitochondrial function is modulating and being modulated by innate immune signaling. Further, cell biologic analyses have uncovered the dynamic relocalization of key components involved in cytosolic viral recognition and signaling to the mitochondria, as well as the mobilization of mitochondria to the sites of viral replication. In this review, we provide an integrated view of how cellular stress and signals following cytosolic viral recognition are intimately linked and coordinated at the mitochondria. We incorporate recent findings into our current understanding of the role of mitochondrial function in antiviral immunity and suggest the existence of a 'mitoxosome', a mitochondrial oxidative signalosome where multiple pathways of viral recognition and cellular stress converge on the surface of the mitochondria to facilitate a coordinated antiviral response.
View details for DOI 10.1111/j.1600-065X.2011.01038.x
View details for Web of Science ID 000295016800017
View details for PubMedID 21884179
Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2009; 106 (8): 2770-2775
Innate immunity to viral infection is initiated within the infected cells through the recognition of unique viral signatures by pattern recognition receptors (PRRs) that mediate the induction of potent antiviral factor, type I interferons (IFNs). Infection with RNA viruses is recognized by the members of the retinoic acid inducible gene I (RIG-I)-like receptor (RLR) family in the cytosol. Our recent study demonstrates that IFN production in response to RNA viral ligands is increased in the absence of autophagy. The process of autophagy functions as an internal cleanup crew within the cell, shuttling damaged cellular organelles and long-lived proteins to the lysosomes for degradation. Our data show that the absence of autophagy leads to the amplification of RLR signaling in two ways. First, in the absence of autophagy, mitochondria accumulate within the cell leading to the buildup of mitochondrial associated protein, IPS-1, a key signaling protein for RLRs. Second, damaged mitochondria that are not degraded in the absence of autophagy provide a source of reactive oxygen species (ROS), which amplify RLR signaling in Atg5 knockout cells. Our study provides the first link between ROS and cytosolic signaling mediated by the RLRs, and suggests the importance of autophagy in the regulation of signaling emanating from mitochondria.
View details for DOI 10.1073/pnas.0807694106
View details for Web of Science ID 000268205300030
View details for PubMedID 19571662
Autophagy and Innate Recognition Systems
AUTOPHAGY IN INFECTION AND IMMUNITY
2009; 335: 107-121
Autophagy is a highly conserved process that maintains homeostasis by clearing damaged organelles and long-lived proteins. The consequences of deficiency in autophagy manifest in a variety of pathological states including neurodegenerative diseases, inflammatory disorders, and cancer. Here, we studied the role of autophagy in the homeostatic regulation of innate antiviral defense. Single-stranded RNA viruses are recognized by the members of the RIG-I-like receptors (RLRs) in the cytosol. RLRs signal through IPS-1, resulting in the production of the key antiviral cytokines, type I IFNs. Autophagy-defective Atg5(-/-) cells exhibited enhanced RLR signaling, increased IFN secretion, and resistance to infection by vesicular stomatitis virus. In the absence of autophagy, cells accumulated dysfunctional mitochondria, as well as mitochondria-associated IPS-1. Reactive oxygen species (ROS) associated with the dysfunctional mitochondria were largely responsible for the enhanced RLR signaling in Atg5(-/-) cells, as antioxidant treatment blocked the excess RLR signaling. In addition, autophagy-independent increase in mitochondrial ROS by treatment of cells with rotenone was sufficient to amplify RLR signaling in WT cells. These data indicate that autophagy contributes to homeostatic regulation of innate antiviral defense through the clearance of dysfunctional mitochondria, and revealed that ROS associated with mitochondria play a key role in potentiating RLR signaling.
View details for DOI 10.1073/pnas.0807694106
View details for Web of Science ID 000263652900055
View details for PubMedID 19196953
Autophagy is an ancient, highly conserved pathway responsible for the lysosomal degradation of cytosolic constituents and organelles that is critical in maintaining cellular homeostasis. Recent studies have illustrated an important interplay between autophagy and the innate immune system. Signaling through innate pattern recognition receptors leads to the induction of autophagy. Autophagy is utilized by the innate immune cells to survey for virus infection through delivery of cytosolic viral replication complexes to the endosomal viral sensors. In another case, key molecules in the autophagy pathway were found to negatively regulate cytosolic sensors of RNA viruses. Moreover, it has recently become apparent that the autophagic machinery is utilized by phagocytic cells for efficient phagocytosis and clearance of extracellular pathogens. These studies shed light on the possibility that molecules classically thought to be dedicated to the process of autophagy may function in important physiological processes independent of autophagy, whereby the double-membrane structures form within the cytosol to enclose organelles and long-lived proteins. In this chapter, we will highlight key findings relevant to the role of the autophagic machinery in the innate immune system.
View details for DOI 10.1007/978-3-642-00302-8_5
View details for Web of Science ID 000273774900005
View details for PubMedID 19802562