Control of adaptive immunity by pattern recognition receptors.

One of the most significant conceptual advances in immunology in recent history is the recognition that signals from the innate immune system are required for induction of adaptive immune responses. Two breakthroughs were critical in establishing this paradigm: the identification of dendritic cells (DCs) as the cellular link between innate and adaptive immunity and the discovery of pattern recognition receptors (PRRs) as a molecular link that controls innate immune activation as well as DC function. Here, we recount the key events leading to these discoveries and discuss our current understanding of how PRRs shape adaptive immune responses, both indirectly through control of DC function and directly through control of lymphocyte function. In this context, we provide a conceptual framework for how variation in the signals generated by PRR activation, in DCs or other cell types, can influence T cell differentiation and shape the ensuing adaptive immune response.

Myeloid C-type lectin receptors in innate immune recognition.

C-type lectin receptors (CLRs) expressed by myeloid cells constitute a versatile family of receptors that play a key role in innate immune recognition. Myeloid CLRs exhibit a remarkable ability to recognize an extensive array of ligands, from carbohydrates and beyond, and encompass pattern-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and markers of altered self. These receptors, classified into distinct subgroups, play pivotal roles in immune recognition and modulation of immune responses. Their intricate signaling pathways orchestrate a spectrum of cellular responses, influencing processes such as phagocytosis, cytokine production, and antigen presentation. Beyond their contributions to host defense in viral, bacterial, fungal, and parasitic infections, myeloid CLRs have been implicated in non-infectious diseases such as cancer, allergies, and autoimmunity. A nuanced understanding of myeloid CLR interactions with endogenous and microbial triggers is starting to uncover the context-dependent nature of their roles in innate immunity, with implications for therapeutic intervention.

Plant cell wall-mediated disease resistance: Current understanding and future perspectives.

Beyond their function as structural barriers, plant cell walls are essential elements for the adaptation of plants to environmental conditions. Cell walls are dynamic structures whose composition and integrity can be altered in response to environmental challenges and developmental cues. These wall changes are perceived by plant sensors/receptors to trigger adaptative responses during development and upon stress perception. Plant cell wall damage caused by pathogen infection, wounding, or other stresses leads to the release of wall molecules, such as carbohydrates (glycans), that function as damage-associated molecular patterns (DAMPs). DAMPs are perceived by the extracellular ectodomains (ECDs) of pattern recognition receptors (PRRs) to activate pattern-triggered immunity (PTI) and disease resistance. Similarly, glycans released from the walls and extracellular layers of microorganisms interacting with plants are recognized as microbe-associated molecular patterns (MAMPs) by specific ECD-PRRs triggering PTI responses. The number of oligosaccharides DAMPs/MAMPs identified that are perceived by plants has increased in recent years. However, the structural mechanisms underlying glycan recognition by plant PRRs remain limited. Currently, this knowledge is mainly focused on receptors of the LysM-PRR family, which are involved in the perception of various molecules, such as chitooligosaccharides from fungi and lipo-chitooligosaccharides (i.e., Nod/MYC factors from bacteria and mycorrhiza, respectively) that trigger differential physiological responses. Nevertheless, additional families of plant PRRs have recently been implicated in oligosaccharide/polysaccharide recognition. These include receptor kinases (RKs) with leucine-rich repeat and Malectin domains in their ECDs (LRR-MAL RKs), Catharanthus roseus RECEPTOR-LIKE KINASE 1-LIKE group (CrRLK1L) with Malectin-like domains in their ECDs, as well as wall-associated kinases, lectin-RKs, and LRR-extensins. The characterization of structural basis of glycans recognition by these new plant receptors will shed light on their similarities with those of mammalians involved in glycan perception. The gained knowledge holds the potential to facilitate the development of sustainable, glycan-based crop protection solutions.

A novel C-type lectin protein (BjCTL5) interacts with apoptosis stimulating proteins of p53 (ASPP) to activate NF-κB signaling pathway in primitive chordate.

C-type lectin proteins (CTLs), a group of pattern recognition receptors (PRRs), play pivotal roles in immune responses. However, the signal transduction and regulation of CTLs in cephalochordates have yet to be explored. In this study, we examined the composition of CTLs in Branchiostoma japonicum, identifying a total of 272 CTLs. These CTLs underwent further analysis concerning domain arrangement, tandem and segmental duplication events. A multidomain C-type lectin gene, designated as BjCTL5, encompassing CLECT, KR, CUB, MAM, and SR domains, was the focal point of our investigation. BjCTL5 exhibits ubiquitous expression across all detected tissues and is responsive to stimulation by LPS, mannose, and poly (I:C). The recombinant protein of BjCTL5 can bind to Escherichia coli and Staphylococcus aureus, inducing their agglutination and inhibiting the proliferation of S. aureus. Yeast two-hybrid, CoIP, and confocal immunofluorescence experiments revealed the interaction between BjCTL5 and apoptosis-stimulating proteins of p53, BjASPP. Intriguingly, BjCTL5 was observed to induce the luciferase activity of the NF-κB promoter in HEK293T cells. These results suggested a potential interaction between BjCTL5 and BjASPP, implicating that they involve in the activation of the NF-κB signaling pathway, which provides an evolutionary viewpoint on NF-κB signaling pathway in primitive chordate.

Identification and functional analysis of Toll-like receptor 2 from razor clam Sinonovacula constricta.

Toll-like receptor 2 (TLR2) is a member of TLR family that plays important roles in the innate immune system, such as pathogen recognition and inflammation regulation. In this study, the TLR2 homologue was cloned from razor clam Sinonovacula constricta (denoted as ScTLR2) and its immune function was explored. The full-length cDNA of ScTLR2 comprised 2890 nucleotides with a 5'-UTR of 218 bp, an open reading frame of 2169 bp encoding 722 amino acids and a 3'-UTR of 503 bp. The deduced amino acid of ScTLR2 showed similar structure to TLR2 homologue with a conserved signal peptide, four LRR domains, one LRR-TYP domain, one LRR-CT domain, one transmembrane domain and a conserved TIR domain. ScTLR2 mRNA was detected in all examined tissues with the highest expression in the gill. After Vibrio parahaemolyticus challenge, the mRNA expression of ScTLR2 was significantly induced both in gill and haemocytes. The recombinant ScTLR2-LRR protein could bind all tested PAMPs including LPS, PGN and MAN. Bacterial agglutination assay showed that rScTLR2 could agglutinate the six tested bacteria with a calcium dependent manner. More importantly, ScTLR2 silencing by siRNA transfection could significantly depress the mRNA expression of Myd88, NF-κB, Tollip, IRF1, and IRF8. The survival rate of S. constricta was markedly decreased after V. parahaemolyticus challenge under this condition. Our current study demonstrated that ScTLR2 served as a pattern recognition receptor to induce immune response against invasive pathogen.

A pattern recognition receptor interleukin-1 receptor is involved in reproductive immunity in Macrobrachium nipponense ovary.

The family of TIR domain-containing receptors includes numerous proteins involved in innate immunity. In this study, a member of this family was characterized from the ovary of the oriental river prawn Macrobrachium nipponense and identified as interleukin-1 receptor (MnIL-1R). Meanwhile, to elucidate the conservation of IL-1R, its orthologous were identified in several crustacean species as well. In addition, the expression pattern of MnIL-1R in various adult tissues and post different pathogen-associated molecular patterns (PAMPs) challenge in ovary was analyzed with qRT-PCR technology. Finally, the roles of MnIL-1R in the ovary were analyzed by RNAi technology. The main results are as follows: (1) MnIL-1R comprises a 1785 bp ORF encoding 594 amino acids and is structurally composed of five domains: a signal peptide, two immunoglobulin (IG) domains, a transmembrane region, and a TIR-2 domain; (2) the TIR domain showed a high conservation among analyzed crustacean species; (3) MnIL-1R is widely detected in all tested tissues including ovary; (4) MnIL-1R showed a positive response to challenges with LPS, PGN, and polyI:C in the ovary; (5) its IG domain showed strong binding ability to LPS and PGN, confirming its role as a pattern recognition receptor; (6) the expression patterns of several members of the Toll signaling pathway (Myd88, TRAF-6, Dorsal, and Relish) was similar to that of MnIL-1R after challenges with LPS, PGN, and polyI:C in the ovary; (7) the silencing of MnIL-1R resulted in down-regulation of theses gene' (Myd88, TRAF-6, Dorsal, and Relish) expression level in the ovary. These results suggest that MnIL-1R can activate the Toll signaling pathway in the ovary by directly recognizing LPS and PGN through its IG domain, thereby contributing to the immune response in the ovary of M. nipponense.

LORE receptor homomerization is required for 3-hydroxydecanoic acid-induced immune signaling and determines the natural variation of immunosensitivity within the Arabidopsis genus.

The S-domain-type receptor-like kinase (SD-RLK) LIPOOLIGOSACCHARIDE-SPECIFIC REDUCED ELICITATION (LORE) from Arabidopsis thaliana is a pattern recognition receptor that senses medium-chain 3-hydroxy fatty acids, such as 3-hydroxydecanoic acid (3-OH-C10:0), to activate pattern-triggered immunity. Here, we show that LORE homomerization is required to activate 3-OH-C10:0-induced immune signaling. Fluorescence lifetime imaging in Nicotiana benthamiana demonstrates that AtLORE homomerizes via the extracellular and transmembrane domains. Co-expression of AtLORE truncations lacking the intracellular domain exerts a dominant negative effect on AtLORE signaling in both N. benthamiana and A. thaliana, highlighting that homomerization is essential for signaling. Screening for 3-OH-C10:0-induced reactive oxygen species production revealed natural variation within the Arabidopsis genus. Arabidopsis lyrata and Arabidopsis halleri do not respond to 3-OH-C10:0, although both possess a putative LORE ortholog. Both LORE orthologs have defective extracellular domains that bind 3-OH-C10:0 to a similar level as AtLORE, but lack the ability to homomerize. Thus, ligand binding is independent of LORE homomerization. Analysis of AtLORE and AlyrLORE chimera suggests that the loss of AlyrLORE homomerization is caused by several amino acid polymorphisms across the extracellular domain. Our findings shed light on the activation mechanism of LORE and the loss of 3-OH-C10:0 perception within the Arabidopsis genus.

SfMBP: A novel microbial binding protein and pattern recognition receptor in the fall armyworm, Spodoptera frugiperda (Lepidoptera: Noctuidae).

The fall armyworm, Spodoptera frugiperda, poses a significant threat as a highly destructive agricultural pest in many countries. Understanding the complex interplay between the insect immune system and entomopathogens is critical for optimizing biopesticide efficacy. In this study, we identified a novel microbial binding protein, SfMBP, in S. frugiperda. However, the specific role of SfMBP in the immune response of S. frugiperda remains elusive. Encoded by the LOC118269163 gene, SfMBP shows significant induction in S. frugiperda larvae infected with the entomopathogen Beauveria bassiana. Consisting of 115 amino acids with a signal peptide, an N-terminal flexible region and a C-terminal ß-sheet, SfMBP lacks any known functional domains. It is expressed predominantly during early larval stages and in the larval epidermis. Notably, SfMBP is significantly induced in larvae infected with bacteria and fungi and in SF9 cells stimulated by peptidoglycan. While recombinant SfMBP (rSfMBP) does not inhibit bacterial growth, it demonstrates binding capabilities to bacteria, fungal spores, peptidoglycan, lipopolysaccharides, and polysaccharides. This binding is inhibited by monosaccharides and EDTA. Molecular docking reveals potential Zn2+-interacting residues and three cavities. Furthermore, rSfMBP induces bacterial agglutination in the presence of Zn2+. It also binds to insect hemocytes and SF9 cells, enhancing phagocytosis and agglutination responses. Injection of rSfMBP increased the survival of S. frugiperda larvae infected with B. bassiana, whereas blocking SfMBP with the antibody decreased survival. These results suggest that SfMBP acts as a pattern recognition receptor that enhances pathogen recognition and cellular immune responses. Consequently, this study provides valuable insights for the development of pest control measures.

Unlocking Nature's Defense: Plant Pattern Recognition Receptors as Guardians Against Pathogenic Threats.

Embedded in the plasma membrane of plant cells, receptor kinases (RKs) and receptor proteins (RPs) act as key sentinels, responsible for detecting potential pathogenic invaders. These proteins were originally characterized more than three decades ago as disease resistance (R) proteins, a concept that was formulated based on Harold Flor's gene-for-gene theory. This theory implies genetic interaction between specific plant R proteins and corresponding pathogenic effectors, eliciting effector-triggered immunity (ETI). Over the years, extensive research has unraveled their intricate roles in pathogen sensing and immune response modulation. RKs and RPs recognize molecular patterns from microbes as well as dangers from plant cells in initiating pattern-triggered immunity (PTI) and danger-triggered immunity (DTI), which have intricate connections with ETI. Moreover, these proteins are involved in maintaining immune homeostasis and preventing autoimmunity. This review showcases seminal studies in discovering RKs and RPs as R proteins and discusses the recent advances in understanding their functions in sensing pathogen signals and the plant cell integrity and in preventing autoimmunity, ultimately contributing to a robust and balanced plant defense response. [Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 "No Rights Reserved" license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2024.

DAMPs and radiation injury.

The heightened risk of ionizing radiation exposure, stemming from radiation accidents and potential acts of terrorism, has spurred growing interests in devising effective countermeasures against radiation injury. High-dose ionizing radiation exposure triggers acute radiation syndrome (ARS), manifesting as hematopoietic, gastrointestinal, and neurovascular ARS. Hematopoietic ARS typically presents with neutropenia and thrombocytopenia, while gastrointestinal ARS results in intestinal mucosal injury, often culminating in lethal sepsis and gastrointestinal bleeding. This deleterious impact can be attributed to radiation-induced DNA damage and oxidative stress, leading to various forms of cell death, such as apoptosis, necrosis and ferroptosis. Damage-associated molecular patterns (DAMPs) are intrinsic molecules released by cells undergoing injury or in the process of dying, either through passive or active pathways. These molecules then interact with pattern recognition receptors, triggering inflammatory responses. Such a cascade of events ultimately results in further tissue and organ damage, contributing to the elevated mortality rate. Notably, infection and sepsis often develop in ARS cases, further increasing the release of DAMPs. Given that lethal sepsis stands as a major contributor to the mortality in ARS, DAMPs hold the potential to function as mediators, exacerbating radiation-induced organ injury and consequently worsening overall survival. This review describes the intricate mechanisms underlying radiation-induced release of DAMPs. Furthermore, it discusses the detrimental effects of DAMPs on the immune system and explores potential DAMP-targeting therapeutic strategies to alleviate radiation-induced injury.

cGLRs Join Their Cousins of Pattern Recognition Receptor Family to Regulate Immune Homeostasis.

Pattern recognition receptors (PRRs) recognize danger signals such as PAMPs/MAMPs and DAMPs to initiate a protective immune response. TLRs, NLRs, CLRs, and RLRs are well-characterized PRRs of the host immune system. cGLRs have been recently identified as PRRs. In humans, the cGAS/STING signaling pathway is a part of cGLRs. cGAS recognizes cytosolic dsDNA as a PAMP or DAMP to initiate the STING-dependent immune response comprising type 1 IFN release, NF-κB activation, autophagy, and cellular senescence. The present article discusses the emergence of cGLRs as critical PRRs and how they regulate immune responses. We examined the role of cGAS/STING signaling, a well-studied cGLR system, in the activation of the immune system. The following sections discuss the role of cGAS/STING dysregulation in disease and how immune cross-talk with other PRRs maintains immune homeostasis. This understanding will lead to the design of better vaccines and immunotherapeutics for various diseases, including infections, autoimmunity, and cancers.

Dual phosphorylation of DGK5-mediated PA burst regulates ROS in plant immunity.

Phosphatidic acid (PA) and reactive oxygen species (ROS) are crucial cellular messengers mediating diverse signaling processes in metazoans and plants. How PA homeostasis is tightly regulated and intertwined with ROS signaling upon immune elicitation remains elusive. We report here that Arabidopsis diacylglycerol kinase 5 (DGK5) regulates plant pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). The pattern recognition receptor (PRR)-associated kinase BIK1 phosphorylates DGK5 at Ser-506, leading to a rapid PA burst and activation of plant immunity, whereas PRR-activated intracellular MPK4 phosphorylates DGK5 at Thr-446, which subsequently suppresses DGK5 activity and PA production, resulting in attenuated plant immunity. PA binds and stabilizes the NADPH oxidase RESPIRATORY BURST OXIDASE HOMOLOG D (RBOHD), regulating ROS production in plant PTI and ETI, and their potentiation. Our data indicate that distinct phosphorylation of DGK5 by PRR-activated BIK1 and MPK4 balances the homeostasis of cellular PA burst that regulates ROS generation in coordinating two branches of plant immunity.

Largemouth bass galectin, MsGal-9: Mediating various functions as a pattern recognition receptor and a potential damage-associated molecular pattern.

Galectins are lectins that bind to ß-galactose and are widely expressed in immune system tissues, playing pivotal roles in innate immunity through their conserved carbohydrate-recognition domains (CRDs). In this present investigation, a tandem-repeat galectin was discovered in the largemouth bass, Micropterus salmoides (designated as MsGal-9). The open reading frame of MsGal-9 encodes two CRDs, each containing two consensus motifs that are essential for ligand binding. MsGal-9 is expressed in various tissues of the largemouth bass, with particularly high expression levels in the liver and spleen. The full-length form of MsGal-9, as well as the N-terminal (MsGal-9-N) and C-terminal (MsGal-9-C) CRDs, were individually recombined. Their ability for nonself recognition was studied. The three recombinant proteins were able to bind to glucan (GLU), peptidoglycan (PGN), and lipopolysaccharide (LPS), with MsGal-9 displaying the highest binding activity. Furthermore, rMsGal-9-N exhibited higher binding activity towards GLU in comparison to rMsGal-9-C. Further investigations revealed that the full-length rMsGal-9 could significantly bind to Gram-positive bacteria, Gram-negative bacteria, and fungi, while rMsGal-9-C specifically bound to Escherichia coli. However, rMsGal-9-N did not exhibit significant binding activity towards any microbes. These findings indicate that MsGal-9 requires both CRDs to cooperate in order to fulfill its nonself recognition function. All three recombinant proteins demonstrated agglutination activity towards various microbes, with MsGal-9 and MsGal-9-N displaying a similar broad binding spectrum, while MsGal-9-C agglutinated three types of bacteria. Moreover, both MsGal-9 and MsGal-9-N were capable of coagulating largemouth bass red blood cells, whereas MsGal-9-C lacked this ability. However, MsGal-9-C played a significant role in enhancing the encapsulation of leukocytes in comparison to MsGal-9-N. All three proteins acted as potential damage-associated molecular patterns (DAMPs), inducing apoptosis in leukocytes.

Downregulation of pattern recognition receptors on macrophages involved in aggravation of endometriosis.

PROBLEM: In women of reproductive age, endometriosis may contribute to dysmenorrhea, chronic pelvic pain, dyspareunia, infertility, adenomyosis, and endometrial ovarian cyst (EOC). Recent studies have shown that chronic inflammation occurs in the pelvis of endometriosis patients and that this inflammation is exacerbated by immunosuppression, leading to survival endometrial debris. However, the detailed immunological mechanisms underlying the aggravation of inflammation and immunosuppression in endometriosis patients remain unclear. METHOD OF STUDY: We investigate the alarmins (high-mobility group box-1, IL-33, IL-1α, and S100B protein), proinflammatory cytokines (IL-6 and IL-1ß), and immune cells (CD8+ T cells, CD4+ T cells, natural killer cells, natural killer T cells, dendritic cells, and macrophages) in peritoneal fluid of patients with EOC using enzyme-linked immunosorbent assay, electrochemiluminescence, and flow cytometry. Then, we analyzed the correlation between these factors and the aggravating indicators of endometriosis, tumor size and revised American Society for Reproductive Medicine (r-ASRM) score. RESULTS: Unexpectedly, there was no correlation between each alarmin level and aggravating indicators. However, the expression of pattern recognition receptors, toll-like receptor 4, and receptor of advanced glycation end-products on macrophages was inversely correlated with aggravating indicators. CONCLUSIONS: The aggravation of endometriosis is associated with a decrease in alarmin receptors but not alarmin levels. Investigation of innate immune systems, such as alarmins and their receptors, may help elucidate new mechanisms of endometriosis.

The entanglement of DNA damage and pattern recognition receptor signaling.

Cells are under constant pressure to suppress DNA damage originating from both exogenous and endogenous sources. Cellular responses to DNA damage help to prevent mutagenesis and cell death that arises when DNA damage is either left unrepaired or repaired inaccurately. During the "acute phase" of DNA damage signaling, lesions are recognized, processed, and repaired to restore the primary DNA sequence whilst cell cycle checkpoints delay mitotic progression, cell death and the propagation of errors to daughter cells. Increasingly, there is recognition of a "chronic phase" of DNA damage signaling, exemplified by the secretion of dozens of cytokines days after the inciting damage event. In this review, we focus on the cellular origin of these chronic responses, the molecular pathways that control them and the increasing appreciation for the interconnection between acute and chronic DNA damage responses.

Releasing hidden MAMPs from precursor proteins in plants.

The recognition of pathogens by plants at the cell surface is crucial for activating plant immunity. Plants employ pattern recognition receptors (PRRs) to detect microbe-associated molecular patterns (MAMPs). However, our knowledge of the release of peptide MAMPs from their precursor proteins is very limited. Here, we explore seven protein precursors of well-known MAMP peptides and discuss the likelihood of processing being required for their recognition based on structural models and public knowledge. This analysis indicates the existence of multiple extracellular events that are likely pivotal for pathogen perception but remain to be uncovered.

The prodomain of Arabidopsis metacaspase 2 positively regulates immune signaling mediated by pattern-recognition receptors.

Metacaspases (MCs) are structural homologs of mammalian caspases found in plants, fungi, and protozoa. Type-I MCs carry an N-terminal prodomain, the function of which is unclear. Through genetic analysis of Arabidopsis mc2-1, a T-DNA insertion mutant of MC2, we demonstrated that the prodomain of metacaspase 2 (MC2) promotes immune signaling mediated by pattern-recognition receptors (PRRs). In mc2-1, immune responses are constitutively activated. The receptor-like kinases (RLKs) BAK1/BKK1 and SOBIR1 are required for the autoimmune phenotype of mc2-1, suggesting that immune signaling mediated by the receptor-like protein (RLP)-type PRRs is activated in mc2-1. A suppressor screen identified multiple mutations in the first exon of MC2, which suppress the autoimmunity in mc2-1. Further analysis revealed that the T-DNA insertion at the end of exon 1 of MC2 causes elevated expression of the MC2 prodomain, and overexpression of the MC2 prodomain in wild-type (WT) plants results in the activation of immune responses. The MC2 prodomain interacts with BIR1, which inhibits RLP-mediated immune signaling by interacting with BAK1, suggesting that the MC2 prodomain promotes plant defense responses by interfering with the function of BIR1. Our study uncovers an unexpected function of the prodomain of a MC in plant immunity.

Understanding nucleic acid sensing and its therapeutic applications.

Nucleic acid sensing is involved in viral infections, immune response-related diseases, and therapeutics. Based on the composition of nucleic acids, nucleic acid sensors are defined as DNA or RNA sensors. Pathogen-associated nucleic acids are recognized by membrane-bound and intracellular receptors, known as pattern recognition receptors (PRRs), which induce innate immune-mediated antiviral responses. PRR activation is tightly regulated to eliminate infections and prevent abnormal or excessive immune responses. Nucleic acid sensing is an essential mechanism in tumor immunotherapy and gene therapies that target cancer and infectious diseases through genetically engineered immune cells or therapeutic nucleic acids. Nucleic acid sensing supports immune cells in priming desirable immune responses during tumor treatment. Recent studies have shown that nucleic acid sensing affects the efficiency of gene therapy by inhibiting translation. Suppression of innate immunity induced by nucleic acid sensing through small-molecule inhibitors, virus-derived proteins, and chemical modifications offers a potential therapeutic strategy. Herein, we review the mechanisms and regulation of nucleic acid sensing, specifically covering recent advances. Furthermore, we summarize and discuss recent research progress regarding the different effects of nucleic acid sensing on therapeutic efficacy. This study provides insights for the application of nucleic acid sensing in therapy.

Mitochondrial nucleic acids in innate immunity and beyond.

Mitochondria participate in a wide range of cellular processes. One essential function of mitochondria is to be a platform for antiviral signaling proteins during the innate immune response to viral infection. Recently, studies have revealed that mitochondrion-derived DNAs and RNAs are recognized as non-self molecules and act as immunogenic ligands. More importantly, the cytosolic release of these mitochondrial nucleic acids (mt-NAs) is closely associated with the pathogenesis of human diseases accompanying aberrant immune activation. The release of mitochondrial DNAs (mtDNAs) via BAX/BAK activation and/or VDAC1 oligomerization activates the innate immune response and inflammasome assembly. In addition, mitochondrial double-stranded RNAs (mt-dsRNAs) are sensed by pattern recognition receptors in the cytosol to induce type I interferon expression and initiate apoptotic programs. Notably, these cytosolic mt-NAs also mediate adipocyte differentiation and contribute to mitogenesis and mitochondrial thermogenesis. In this review, we summarize recent studies of innate immune signaling pathways regulated by mt-NAs, human diseases associated with mt-NAs, and the emerging physiological roles of mt-NAs.

BIK1 protein homeostasis is maintained by the interplay of different ubiquitin ligases in immune signaling.

Pathogen-associated molecular patterns (PAMPs) trigger plant innate immunity that acts as the first line of inducible defense against pathogen infection. A receptor-like cytoplasmic kinase BOTRYTIS-INDUCED KINASE 1 (BIK1) functions as a signaling hub immediately downstream of multiple pattern recognition receptors (PRRs). It is known that PLANT U-BOX PROTEIN 25 (PUB25) and PUB26 ubiquitinate BIK1 and mediate BIK1 degradation. However, how BIK1 homeostasis is maintained is not fully understood. Here, we show that two closely related ubiquitin ligases, RING DOMAIN LIGASE 1 (RGLG1) and RGLG2, preferentially associate with the hypo-phosphorylated BIK1 and promote the association of BIK1 with the co-receptor for several PRRs, BRI1-ASSOCIATED RECEPTOR KINASE1 (BAK1). PUB25 interacts with RGLG2 and mediates its degradation. In turn, RGLG2 represses the ubiquitin ligase activity of PUB25. RGLG1/2 suppress PUB25-mediated BIK1 degradation, promote BIK1 protein accumulation, and positively regulate immune signaling in a ubiquitin ligase activity-dependent manner. Our work reveals how BIK1 homeostasis is maintained by the interplay of different ubiquitin ligases.