Pathogen-Induced Autophagy Signaling in Innate Immunity

Faure, Mathias; Lafont, Frank

doi:10.1159/000350918

Cited by 32 publications

(22 citation statements)

References 132 publications

(185 reference statements)

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“…LPS, a major component of the outer membrane of Gram-negative bacteria, has been recently considered as a critical stimulus of adipose tissue inflammation and a regulator of autophagy. LPS has been known to bind TLR2 and TLR4 on the plasma membrane with the involvement of MD-2 to activate an immune response and induce inflammation (60). The data from human studies has shown that obese subjects have altered gut microflora, leading to the elevation of circulating LPS (61).…”

Section: Discussionmentioning

confidence: 99%

Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes

Guo

Zhao

Qiu

et al. 2016

Journal of Lipid Research

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Aging is a risk factor for the development of chronic metabolic diseases such as type 2 diabetes, cardiovascular disease, neurodegenerative disease, and cancer. These aging-related diseases are known to be clustered together; aging-associated neurodegenerative disorders frequently coincide with type 2 diabetes, insulin resistance, obesity, and metabolic syndrome. This suggests that neurodegenerative disorders and type 2 diabetes share common genetic and metabolic features. Therefore, studying the role of the gene that contributes to neurodegenerative diseases in obesity and diabetes is of particular importance, as it may provide a clue for the pathological mechanism of the development of aging-related diseases. Intensive investigation on the underlying mechanisms of cellular aging has suggested that autophagy-lysosome and mitochondrial function plays an essential role in the regulation of cellular homeostasis and health (1). The autophagy-lysosome system is one of the main intracellular proteolytic systems that is responsible for the clearance of unwanted intracellular macromolecules and organelles (2). Cellular aging is associated with the disruption of this homeostatic mechanism, leading to the accumulation of oxidized/misfolded proteins, lipids, and damaged organelles (3). However, the genes and proteins that regulate autophagy-lysosomal activation and contribute to cellular aging remain largely unidentified.Autophagy is a highly regulated process that is inducible by nutrient deprivation and cellular stress. During nutrient deprivation, multiple signaling pathways cooperate to Abstract In this study, we investigated the role and mechanism of Niemann-Pick type C (NPC)2 in regulating lysosomal activity, mitophagy, and mitochondrial function in adipocytes. We found that knocking down NPC2 impaired lysosomal activity, as evidenced by the reduced mature cathepsin B, the increased accumulation of light chain 3 (LC3) and p62, and the decreased autophagic flux. In NPC2-knockdown (kd) adipocytes, the starvation-induced conversion of LC3-I to LC3-II was abolished. More interestingly, the majority of NPC2 was found in the mitochondrial fraction, and NPC2 deficiency led to impaired autophagic flux and decreased induction of LC3-II in the mitochondrial fraction during mitochondrial stress. Moreover, cellular respiration profiling revealed that NPC2-kd adipocytes had significantly decreased basal/maximal respiration and mitochondrial gene expression compared with scrambled cells, suggesting mitochondrial dysfunction. Additionally, we found that the mitochondrial recruitment of LC3-II induced by lipopolysaccharide (LPS), but not TNF, was blunted in NPC2-kd adipocytes. Most intriguingly, NPC2-kd selectively diminished LPS-induced NFB and ERK1/2 phosphorylation and the expression of pro-inflammatory genes, indicating that tolllike receptor signaling activation is impaired in the absence of NPC2. Our results suggest that NPC2 is in a mitochondrially associated autophagosome and plays an important role in regulating mitophag...

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Section: Discussionmentioning

confidence: 99%

Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes

Guo

Zhao

Qiu

et al. 2016

Journal of Lipid Research

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“…Autophagy not only is a regulated catabolic process but also plays an essential role in other signal pathways such as apoptosis and innate immunity (47)(48)(49). As NDV induced apoptosis and host immune response in vitro and in vivo, it is reasonable to conclude that autophagy might affect NDV replication through regulation of other pathways.…”

Section: Figmentioning

confidence: 99%

Autophagy Benefits the Replication of Newcastle Disease Virus in Chicken Cells and Tissues

Sun

Ding

et al. 2014

J Virol

102

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bNewcastle disease virus (NDV) is an important avian pathogen. We previously reported that NDV triggers autophagy in U251 glioma cells, resulting in enhanced virus replication. In this study, we investigated whether NDV triggers autophagy in chicken cells and tissues to enhance virus replication. We demonstrated that NDV infection induced steady-state autophagy in chickenderived DF-1 cells and in primary chicken embryo fibroblast (CEF) cells, evident through increased double-or single-membrane vesicles, the accumulation of green fluorescent protein (GFP)-LC3 dots, and the conversion of LC3-I to LC3-II. In addition, we measured autophagic flux by monitoring p62/SQSTM1 degradation, LC3-II turnover, and GFP-LC3 lysosomal delivery and proteolysis, to confirm that NDV infection induced the complete autophagic process. Inhibition of autophagy by pharmacological inhibitors and RNA interference reduced virus replication, indicating an important role for autophagy in NDV infection. Furthermore, we conducted in vivo experiments and observed the conversion of LC3-I to LC3-II in heart, liver, spleen, lung, and kidney of NDV-infected chickens. Regulation of the induction of autophagy with wortmannin, chloroquine, or starvation treatment affects NDV production and pathogenesis in tissues of both lung and intestine; however, treatment with rapamycin, an autophagy inducer of mammalian cells, showed no detectable changes in chicken cells and tissues. Moreover, administration of the autophagy inhibitor wortmannin increased the survival rate of NDV-infected chickens. Our studies provide strong evidence that NDV infection induces autophagy which benefits NDV replication in chicken cells and tissues.

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“…In addition, autophagy emerges as a component of innate immunity as it can destroy infectious viruses or viral components essential for viral replication or assembly, a process referred to as virophagy, linking virus detection to antiviral innate immune signals or participating in the regulation of immune and inflammatory cell response [107,108]. In this circumstance, HDAC6 facilitates aggresome formation and autophagic degradation for the clearance of intracellular invasive viruses or viral proteins.…”

Section: Controlling Antiviral Immune Responsesmentioning

confidence: 99%

Cellular defence or viral assist: the dilemma of HDAC6

Zheng

Jiang

et al. 2017

Journal of General Virology

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Histone deacetylase 6 (HDAC6) is a unique cytoplasmic deacetylase that regulates various important biological processes by preventing protein aggregation and deacetylating different non-histone substrates including tubulin, heat shock protein 90, cortactin, retinoic acid inducible gene I and b-catenin. Growing evidence has indicated a dual role for HDAC6 in viral infection and pathogenesis: HDAC6 may represent a host defence mechanism against viral infection by modulating microtubule acetylation, triggering antiviral immune response and stimulating protective autophagy, or it may be hijacked by the virus to enhance proinflammatory response. In this review, we will highlight current data illustrating the complexity and importance of HDAC6 in viral pathogenesis. We will summarize the structure and functional specificity of HDAC6, and its deacetylaseand ubiquitin-dependent activity in key cellular events in response to virus infection. We will also discuss how HDAC6 exerts its direct or indirect histone modification ability in viral lytic-latency switch.

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Pathogen-Induced Autophagy Signaling in Innate Immunity

Cited by 32 publications

References 132 publications

Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes

Niemann-Pick type C2 deficiency impairs autophagy-lysosomal activity, mitochondrial function, and TLR signaling in adipocytes

Autophagy Benefits the Replication of Newcastle Disease Virus in Chicken Cells and Tissues

Cellular defence or viral assist: the dilemma of HDAC6

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