Mechanisms of MAVS Regulation at the Mitochondrial Membrane

Mitochondria have emerged as critical platforms for antiviral innate immune signaling. This is due in large part to the mitochondrial localization of the innate immune signaling adaptor MAVS (mitochondrial antiviral signaling protein), which coordinates signals received from two independent cytosolic pathogen recognition receptors (PRRs) to induce antiviral genes. The existence of a shared adaptor for two central PRRs presents an ideal target by which the host cell can prevent cellular damage induced by uncontrolled inflammation through alteration of MAVS expression and/or signaling. In this review, we focus on the MAVS regulome and review the cellular factors that regulate MAVS by (1) protein–protein interactions, (2) alterations in mitochondrial dynamics, and/or (3) post-translational modifications.     

Mitochondria-derived reactive oxygen species negatively regulates immune innate signaling pathways triggered by a DNA virus, but not by an RNA virus

Reactive oxygen species (ROS) are crucial secondary messengers of signaling pathways. Redox-dependent signaling events have been previously described in the innate immune response. However, the mechanism by which ROS modulates anti-viral innate immune signaling is not fully clarified. Here, we report that mitochondria-derived ROS differentially regulate the innate response to DNA and RNA viruses (herpes simplex virus (HSV) and Sendai virus (SeV), respectively), with the cytokine response to HSV being negatively regulated by mitochondrial ROS. Importantly, specific activation of Toll-like receptors (TLRs) and DNA receptors (DNARs) but not retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), led to signaling cascades that were inhibited by mitochondrial ROS production. Thus, localized mitochondrial ROS exerts negative modulation of innate immune responses to the DNA virus HSV-2 but not the RNA virus SeV.     

线粒体损伤相关模式分子与宿主免疫调节

线粒体是真核细胞至关重要的细胞器,参与机体细胞能量代谢和细胞凋亡等多种生物学过程。线粒体还参与机体的天然免疫反应的调节。线粒体不仅可以作为病毒免疫反应的载体,还可以通过产生ROS参与抗菌反应。线粒体受到损伤、刺激后,可释放mtDNA,TFAM,ROS,ATP,心磷脂和甲酰肽等内容物。这些分子可以作为损伤相关模式分子(damage associated molecular patterns, DAMPs)被模式识别受体识别,从而参与宿主的免疫调节。研究表明,线粒体已成为内源性DAMPs的重要来源,在先天性免疫应答以及疾病进展过程中发挥着重要的作用。本文就线粒体来源的损伤相关模式分子在机体免疫调节中的作用进行综述。     

Mitochondrial DNA in the regulation of innate immune responses

Mitochondrion is known as the energy factory of the cell, which is also a unique mammalian organelle and considered to be evolved from aerobic prokaryotes more than a billion years ago. Mitochondrial DNA, similar to that of its bacterial ancestor’s, consists of a circular loop and contains significant number of unmethylated DNA as CpG islands. The innate immune system plays an important role in the mammalian immune response. Recent research has demonstrated that mitochondrial DNA (mtDNA) activates several innate immune pathways involving TLR9, NLRP3 and STING signaling, which contributes to the signaling platforms and results in effector responses. In addition to facilitating antibacterial immunity and regulating antiviral signaling, mounting evidence suggests that mtDNA contributes to inflammatory diseases following cellular damage and stress. Therefore, in addition to its well-appreciated roles in cellular metabolism and energy production, mtDNA appears to function as a key member in the innate immune system. Here, we highlight the emerging roles of mtDNA in innate immunity.     

线粒体——抗病毒感染的重要细胞器

线粒体不但是细胞内重要的能量提供者,而且在病毒感染后引起的细胞凋亡中扮演着极为重要的角色。新发现的线粒体抗病毒蛋白将线粒体与先天性免疫联系起来,这也意味着宿主免疫反应和细胞凋亡可能与线粒体密切相关,显示出线粒体在细胞内的重要作用,提示应加强对线粒体在抗病毒感染和治疗等方面作用的研究。     

HSV infection induces production of ROS, which potentiate signaling from pattern recognition receptors: role for S-glutathionylation of TRAF3 and 6

The innate immune response constitutes the first line of defense against infections. Pattern recognition receptors recognize pathogen structures and trigger intracellular signaling pathways leading to cytokine and chemokine expression. Reactive oxygen species (ROS) are emerging as an important regulator of some of these pathways. ROS directly interact with signaling components or induce other post-translational modifications such as S-glutathionylation, thereby altering target function. Applying live microscopy, we have demonstrated that herpes simplex virus (HSV) infection induces early production of ROS that are required for the activation of NF-κB and IRF-3 pathways and the production of type I IFNs and ISGs. All the known receptors involved in the recognition of HSV were shown to be dependent on the cellular redox levels for successful signaling. In addition, we provide biochemical evidence suggesting S-glutathionylation of TRAF family proteins to be important. In particular, by performing mutational studies we show that S-glutathionylation of a conserved cysteine residue of TRAF3 and TRAF6 is important for ROS-dependent activation of innate immune pathways. In conclusion, these findings demonstrate that ROS are essential for effective activation of signaling pathways leading to a successful innate immune response against HSV infection.     

Paramyxovirus Activation and Inhibition of Innate Immune Responses

Paramyxoviruses represent a remarkably diverse family of enveloped nonsegmented negative-strand RNA viruses, some of which are the most ubiquitous disease-causing viruses of humans and animals. This review focuses on paramyxovirus activation of innate immune pathways, the mechanisms by which these RNA viruses counteract these pathways, and the innate response to paramyxovirus infection of dendritic cells (DC). Paramyxoviruses are potent activators of extracellular complement pathways, a first line of defense that viruses must face during natural infections. We discuss mechanisms by which these viruses activate and combat complement to delay neutralization. Once cells are infected, virus replication drives type I interferon (IFN) synthesis that has the potential to induce a large number of antiviral genes. Here we describe four approaches by which paramyxoviruses limit IFN induction: by limiting synthesis of IFN-inducing aberrant viral RNAs, through targeted inhibition of RNA sensors, by providing viral decoy substrates for cellular kinase complexes, and through direct blocking of the IFN promoter. In addition, paramyxoviruses have evolved diverse mechanisms to disrupt IFN signaling pathways. We describe three general mechanisms, including targeted proteolysis of signaling factors, sequestering cellular factors, and upregulation of cellular inhibitors. DC are exceptional cells with the capacity to generate adaptive immunity through the coupling of innate immune signals and T cell activation. We discuss the importance of innate responses in DC following paramyxovirus infection and their consequences for the ability to mount and maintain antiviral T cells.     

The insect cellular immune response

The innate immune system of insects is divided into humoral defenses that include the production of soluble effector molecules and cellular defenses like phagocytosis and encapsulation that are mediated by hemocytes. This review summarizes current understand- ing of the cellular immune response. Insects produce several terminally differentiated types of hemocytes that are distinguished by morphology, molecular and antigenic markers, and function. The differentiated hemocytes that circulate in larval or nymphal stage insects arise from two sources： progenitor cells produced during embryogenesis and mesodermally derived hematopoietic organs. Regulation of hematopoiesis and hemocyte differentiation also involves several different signaling pathways. Phagocytosis and encapsulation require that hemocytes first recognize a given target as foreign followed by activation of downstream signaling and effector responses. A number of humoral and cellular receptors have been identified that recognize different microbes and multicellular parasites. In turn, activation of these receptors stimulates a number of signaling pathways that regulate different hemocyte functions. Recent studies also identify hemocytes as important sources Of a number of humoral effector molecules required for killing different foreign invaders.     

微小RNA在朊病毒病等神经退行性疾病中的研究进展

朊病毒病是一类具有传染性、不可逆且致命的神经退行性疾病,其致病机制为体内正常编码的细胞型朊蛋白(cellular prion protein,PrP~C)构象发生变化,形成了具有感染性的异常痒病型朊病毒(scrapie prion protein,PrP~(Sc)),但具体机制不清楚,目前为止尚无有效治疗方法。微小RNA(microRNA,miRNA)可在转录水平调控细胞蛋白表达,对神经系统发育及功能起重要作用。近年来,对一些特定miRNA在朊病毒病中相应调控机制、自发免疫、炎症信号转导及靶基因预测方面的研究可为治疗朊病毒病提供新的角度。本文就miRNA在朊病毒病发生中的相关研究进展进行综述,并详细探讨其中研究较为深入的miRNA。     

Stimulator of interferon genes (STING): A “new chapter” in virus-associated cancer research. Lessons from wild-derived mouse models of innate immunity

Thanks to the numerous studies that have been carried out recently in the field of cytosolic DNA sensing, STING (Stimulator of Interferon Genes) is now recognized as a key mediator of innate immune signaling. A substantial body of evidence derived from in vivo mouse models demonstrates that STING-regulated pathways underlie the pathogenesis of many diseases including infectious diseases and cancers. It has also become evident from these studies that STING is a promising therapeutic target for the treatment of cancer. However, mouse strains commonly used for modelling innate immune response against infections or tumors do not allow investigators to accurately reproduce certain specific characteristics of immune response observed in human cells. In this review, we will discuss recent data demonstrating that the use of wild-derived genetically distinct inbred mice as a model for investigation into the innate immunity signaling networks may provide valuable insight into the STING-regulated pathways specific for human cells. The maximum complexity of STING-mediated mechanisms can probably be seen in case of DNA virus-induced carcinogenesis in which STING may perform unexpected biological activities. Therefore, in another part of this review we will summarize emerging data on the role of STING in human DNA virus-related oncopathologies, with particular attention to HPV-associated cervical cancer, aiming to demonstrate that STING indeed “starts a new chapter” in research on this issue and that wild-derived mouse models of STING-mediated response to infections will probably be helpful in finding out molecular basis for clinical observations.     

The human mitochondrial proteome: oxidative stress, protein modifications and oxidative phosphorylation

Mitochondria are one of the most complex of subcellular organelles and play key roles in many cellular functions including energy production, fatty acid metabolism, pyrimidine biosynthesis, calcium homeostasis, and cell signaling. In recent years, we and other groups have attempted to identify the complete set of proteins that are localized to human mitochondria as a way to better understand its cellular functions and how it communicates with other cell compartment in complex signaling pathways such as oxidative stress and apoptosis. Indeed, there is an increasing interest in understanding the molecular details of oxidative stress and the mitochondrial role in this process, as well as assessing how mitochondrial proteins become damaged or posttranslationally modified as a consequence of a major change in a cell's redox status. In this review, we report on the current status of the human mitochondrial proteome with an emphasis towards understanding how mitochondrial proteins, especially the proteins that make up the respiratory chain or oxidative phosphorylation (OXPHOS) enzymes, are modified in various models of age-related diseases such as cancer and Parkinson's disease (PD).     

After the banquet

Mitochondria are highly dynamic organelles of crucial importance to the proper functioning of neuronal, cardiac and other cell types dependent upon aerobic efficiency. Mitochondrial dysfunction has been implicated in numerous human conditions, to include cancer, metabolic diseases, neurodegeneration, diabetes, and aging. In recent years, mitochondrial turnover by macroautophagy (mitophagy) has captured the limelight, due in part to discoveries that genes linked to Parkinson disease regulate this quality control process. A rapidly growing literature is clarifying effector mechanisms that underlie the process of mitophagy; however, factors that regulate positive or negative cellular outcomes have been less studied. Here, we review the literature on two major pathways that together may determine cellular adaptation vs. cell death in response to mitochondrial dysfunction. Mitochondrial biogenesis and mitophagy represent two opposing, but coordinated processes that determine mitochondrial content, structure, and function. Recent data indicate that the capacity to undergo mitochondrial biogenesis, which is dysregulated in disease states, may play a key role in determining cell survival following mitophagy-inducing injuries. The current literature on major pathways that regulate mitophagy and mitochondrial biogenesis is summarized, and mechanisms by which the interplay of these two processes may determine cell fate are discussed. We conclude that in primary neurons and other mitochondrially dependent cells, disruptions in any phase of the mitochondrial recycling process can contribute to cellular dysfunction and disease. Given the emerging importance of crosstalk among regulators of mitochondrial function, autophagy, and biogenesis, signaling pathways that coordinate these processes may contribute to therapeutic strategies that target or regulate mitochondrial turnover and regeneration.     

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.     

Membraneless Organelles and Condensates Orchestrate Innate Immunity Against Viruses

The cellular defense against viruses involves the assembly of oligomers, granules and membraneless organelles (MLOs) that govern the activation of several arms of the innate immune response. Upon interaction with specific pathogen-derived ligands, a number of pattern recognition receptors (PRRs) undergo phase-separation thus triggering downstream signaling pathways. Among other relevant condensates, inflammasomes, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) specks, cyclic GMP-AMP synthase (cGAS) foci, protein kinase R (PKR) clusters, ribonuclease L-induced bodies (RLBs), stress granules (SGs), processing bodies (PBs) and promyelocytic leukemia protein nuclear bodies (PML NBs) play different roles in the immune response. In turn, viruses have evolved diverse strategies to evade the host defense. Viral DNA or RNA, as well as viral proteases or proteins carrying intrinsically disordered regions may interfere with condensate formation and function in multiple ways. In this review we discuss current and hypothetical mechanisms of viral escape that involve the disassembly, repurposing, or inactivation of membraneless condensates that govern innate immunity. We summarize emerging interconnections between these diverse condensates that ultimately determine the cellular outcome.     

昆虫天然免疫相关基因研究进展

在长期进化过程中,昆虫形成了强大的天然免疫防御系统,即体液免疫和细胞免疫。体液免疫主要包括Toll、IMD和JAK/STAT 3条信号通路,通过信号转导及免疫途径调控免疫相关基因的表达,诱导产生抗菌肽和其他效应分子。细胞免疫由血细胞介导,主要完成对病原物的包裹、吞噬和集结等。近年来,昆虫基因组学快速发展,通过生物信息学等方法从昆虫基因组数据中已鉴定到大量免疫相关基因,对这些基因的研究加深了人们对昆虫天然免疫分子机制的认识和理解。根据基因功能,免疫相关基因分为识别、信号转导、调制器、效应分子、黑化反应、RNA干扰和其他基因等7类,这些基因通过互作来调控体液免疫和细胞免疫。本文对昆虫免疫相关基因的分类、功能及家族进化等方面的研究成果进行总结,并对今后昆虫免疫的研究重点进行了展望,以期为昆虫免疫分子机制的研究及开发新的害虫防治策略提供依据。     

Modeling Innate Antiviral Immunity in Physiological Context

An effective innate antiviral response is critical for the mitigation of severe disease and host survival following infection. In vivo, the innate antiviral response is triggered by cells that detect the invading pathogen and then communicate through autocrine and paracrine signaling to stimulate the expression of genes that inhibit viral replication, curtail cell proliferation, or modulate the immune response. In other words, the innate antiviral response is complex and dynamic. Notably, in the laboratory, culturing viruses and assaying viral life cycles frequently utilizes cells that are derived from tissues other than those that support viral replication during natural infection, while the study of viral pathogenesis often employs animal models. In recapitulating the human antiviral response, it is important to consider that variation in the expression and function of innate immune sensors and antiviral effectors exists across species, cell types, and cell differentiation states, as well as when cells are placed in different contexts. Thus, to gain novel insight into the dynamics of the host response and how specific sensors and effectors impact infection kinetics by a particular virus, the model system must be selected carefully. In this review, we briefly introduce key signaling pathways involved in the innate antiviral response and highlight how these differ between systems. We then review the application of tissue-engineered or 3D models for studying the antiviral response, and suggest how these in vitro culture systems could be further utilized to assay physiologically-relevant host responses and reveal novel insight into virus-host interactions.     

Mitochondria in innate immune responses

The innate immune system has a key role in the mammalian immune response. Recent research has demonstrated that mitochondria participate in a broad range of innate immune pathways, functioning as signalling platforms and contributing to effector responses. In addition to regulating antiviral signalling, mounting evidence suggests that mitochondria facilitate antibacterial immunity by generating reactive oxygen species and contribute to innate immune activation following cellular damage and stress. Therefore, in addition to their well-appreciated roles in cellular metabolism and programmed cell death, mitochondria appear to function as centrally positioned hubs in the innate immune system. Here, we review the emerging knowledge about the roles of mitochondria in innate immunity.