A Requirement for Argonaute 4 in Mammalian Antiviral Defense

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The Mitochondrial Protein MAVS Stabilizes p53 to Suppress Tumorigenesis

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Mitochondria in innate immunity

Mitochondria are cellular organelles involved in host-cell metabolic processes and the control of programmed cell death. A direct link between mitochondria and innate immune signalling was first highlighted with the identification of MAVS-a crucial adaptor for RIGI-like receptor signalling-as a mitochondria-anchored protein. Recently, other innate immune molecules, such as NLRX1, TRAF6, NLRP3 and IRGM have been functionally associated with mitochondria. Furthermore, mitochondrial alarmins-such as mitochondrial DNA and formyl peptides-can be released by damaged mitochondria and trigger inflammation. Therefore, mitochondria emerge as a fundamental hub for innate immune signalling.     

Checks and Balances between Autophagy and Inflammasomes during Infection

Autophagy and inflammasome complex assembly are physiological processes that control homeostasis, inflammation, and immunity. Autophagy is a ubiquitous pathway that degrades cytosolic macromolecules or organelles, as well as intracellular pathogens. Inflammasomes are multi-protein complexes that assemble in the cytosol of cells upon detection of pathogen- or danger-associated molecular patterns. A critical outcome of inflammasome assembly is the activation of the cysteine protease caspase-1, which activates the pro-inflammatory cytokine precursors pro-IL-1β and pro-IL-18. Studies on chronic inflammatory diseases, heart diseases, Alzheimer's disease, and multiple sclerosis revealed that autophagy and inflammasomes intersect and regulate each other. In the context of infectious diseases, however, less is known about the interplay between autophagy and inflammasome assembly, although it is becoming evident that pathogens have evolved multiple strategies to inhibit and/or subvert these pathways and to take advantage of their intricate crosstalk. An improved appreciation of these pathways and their subversion by diverse pathogens is expected to help in the design of anti-infective therapeutic interventions.     

BST2 inhibits type I IFN (interferon) signaling by accelerating MAVS degradation through CALCOCO2-directed autophagy

Macroautophagy/autophagy is a conserved lysosomal degradation system that breaks down intracellular material through the formation of double-membrane autophagosomes in eukaryotic cells. Cargo receptors have been shown to play essential roles in capturing and delivering specific substrates into phagophores, the precursors to autophagosomes, for degradation. However, the detailed mechanism underlying selective recognition of the substrates for autophagic degradation remains poorly understood. Recently, we have revealed that IFN (interferon)-induced BST2 recruits the E3 ubiquitin ligase MARCH8 to catalyze the K27-linked ubiquitination of MAVS for CALCOCO2-directed autophagic degradation, hence inhibiting DDX58-mediated type I interferon signaling through a negative feedback loop.     

Degradation of RIG-I following cytomegalovirus infection is independent of apoptosis

Many viruses have evolved strategies to either evade or hijack host cell immune programs, as a means of promoting their own reproduction. For example, the human cytomegalovirus (HCMV) immediate-early protein vMIA/UL37ex1 inhibits host cell apoptosis, and its expression during infection aids virus replication. Here it is shown that stable expression of vMIA/UL37ex1 reduces cleavage of the innate immune response-proteins MAVS and RIG-I by caspases during apoptosis. Unexpectedly, it is demonstrated that RIG-I, but not MAVS, is degraded during HCMV infection. This process occurs in a non-apoptotic manner, and provides new evidence that HCMV may have evolved a unique strategy to evade RIG-I-mediated immune responses.     

运动应激介导线粒体DAMP对先天性免疫的调控作用研究进展

线粒体是先天性免疫的关键调控者,具体表现为:线粒体可以通过释放多种线粒体损伤相关分子模式(damage-associated molecular patterns,DAMPs)来诱发先天性免疫应答,如线粒体DNA(mitochondrial DNA,mtDNA)、线粒体转录因子 A(mitochondrial tran...     

How Mitochondrial Metabolism Contributes to Macrophage Phenotype and Functions

Metabolic reprogramming of cells from the innate immune system is one of the most noteworthy topics in immunological research nowadays. Upon infection or tissue damage, innate immune cells, such as macrophages, mobilize various immune and metabolic signals to mount a response best suited to eradicate the threat. Current data indicate that both the immune and metabolic responses are closely interconnected. On account of its peculiar position in regulating both of these processes, the mitochondrion has emerged as a critical organelle that orchestrates the coordinated metabolic and immune adaptations in macrophages. Significant effort is now underway to understand how metabolic features of differentiated macrophages regulate their immune specificities with the eventual goal to manipulate cellular metabolism to control immunity. In this review, we highlight some of the recent work that place cellular and mitochondrial metabolism in a central position in the macrophage differentiation program.     

Regulation of Mitochondrial Antiviral Signaling (MAVS) Expression and Signaling by the Mitochondria-associated Endoplasmic Reticulum Membrane (MAM) Protein Gp78

In a previous study, we identified the E3 ubiquitin ligase Gp78 by RNAi high-throughput screening as a gene whose depletion restricted enterovirus infection. In the current study, we show that Gp78, which localizes to the ER-mitochondria interface, is a regulator of RIG-I-like receptor (RLR) antiviral signaling. We show that depletion of Gp78 results in a robust decrease of vesicular stomatitis virus (VSV) infection and a corresponding enhancement of type I interferon (IFN) signaling. Mechanistically, we show that Gp78 modulates type I IFN induction by altering both the expression and signaling of the mitochondria-localized RLR adaptor mitochondrial antiviral signaling (MAVS). Expression of mutants of Gp78 that abolish its E3 ubiquitin ligase and its participation in ER-associated degradation (ERAD) lost their ability to degrade MAVS, but surprisingly maintained their ability to repress RLR signaling. In contrast, Gp78 lacking its entire C terminus lost both its ability to degrade MAVS and repress RLR signaling. We show that Gp78 interacts with both the N- and C-terminal domains of MAVS via its C-terminal RING domain, and that this interaction is required to abrogate Gp78-mediated attenuation of MAVS signaling. Our data thus implicate two parallel pathways by which Gp78 regulates MAVS signaling; one pathway requires its E3 ubiquitin ligase and ERAD activity to directly degrade MAVS, whereas the other pathway occurs independently of these activities, but requires the Gp78 RING domain and occurs via a direct association between this region and MAVS.