ABSTRACT
Posttranscriptional control of mRNA regulates various biological processes, including inflammatory and immune responses. RNA-binding proteins (RBPs) bind cis-regulatory elements in the 3' untranslated regions (UTRs) of mRNA and regulate mRNA turnover and translation. In particular, eight RBPs (TTP, AUF1, KSRP, TIA-1/TIAR, Roquin, Regnase, HuR, and Arid5a) have been extensively studied and are key posttranscriptional regulators of inflammation and immune responses. These RBPs sometimes collaboratively or competitively bind the same target mRNA to enhance or dampen regulatory activities. These RBPs can also bind their own 3' UTRs to negatively or positively regulate their expression. Both upstream signaling pathways and microRNA regulation shape the interactions between RBPs and target RNA. Dysregulation of RBPs results in chronic inflammation and autoimmunity. Here, we summarize the functional roles of these eight RBPs in immunity and their associated diseases.
Subject(s)
MicroRNAs , RNA Stability , Animals , Gene Expression Regulation , Humans , MicroRNAs/genetics , RNA, Messenger/genetics , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolismABSTRACT
Toll-like receptors (TLRs) are an evolutionarily conserved family in the innate immune system and are the first line of host defense against microbial pathogens by recognizing pathogen-associated molecular patterns (PAMPs). TLRs, categorized into cell surface and endosomal subfamilies, recognize diverse PAMPs, and structural elucidation of TLRs and PAMP complexes has revealed their intricate mechanisms. TLRs activate common and specific signaling pathways to shape immune responses. Recent studies have shown the importance of post-transcriptional regulation in TLR-mediated inflammatory responses. Despite their protective functions, aberrant responses of TLRs contribute to inflammatory and autoimmune disorders. Understanding the delicate balance between TLR activation and regulatory mechanisms is crucial for deciphering their dual role in immune defense and disease pathogenesis. This review provides an overview of recent insights into the history of TLR discovery, elucidation of TLR ligands and signaling pathways, and their relevance to various diseases.
Subject(s)
Pathogen-Associated Molecular Pattern Molecules , Toll-Like Receptors , Toll-Like Receptors/metabolism , Immunity, Innate/physiology , Signal Transduction , Gene Expression RegulationABSTRACT
Limited infiltration and activity of natural killer (NK) and T cells within the tumor microenvironment (TME) correlate with poor immunotherapy responses. Here, we examined the role of the endonuclease Regnase-1 on NK cell anti-tumor activity. NK cell-specific deletion of Regnase-1 (Reg1ΔNK) augmented cytolytic activity and interferon-gamma (IFN-γ) production in vitro and increased intra-tumoral accumulation of Reg1ΔNK-NK cells in vivo, reducing tumor growth dependent on IFN-γ. Transcriptional changes in Reg1ΔNK-NK cells included elevated IFN-γ expression, cytolytic effectors, and the chemokine receptor CXCR6. IFN-γ induced expression of the CXCR6 ligand CXCL16 on myeloid cells, promoting further recruitment of Reg1ΔNK-NK cells. Mechanistically, Regnase-1 deletion increased its targets, the transcriptional regulators OCT2 and IκBζ, following interleukin (IL)-12 and IL-18 stimulation, and the resulting OCT2-IκBζ-NF-κB complex induced Ifng transcription. Silencing Regnase-1 in human NK cells increased the expression of IFNG and POU2F2. Our findings highlight NK cell dysfunction in the TME and propose that targeting Regnase-1 could augment active NK cell persistence for cancer immunotherapy.
Subject(s)
Interferon-gamma , Killer Cells, Natural , Tumor Microenvironment , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Animals , Interferon-gamma/metabolism , Humans , Mice , Tumor Microenvironment/immunology , Mice, Inbred C57BL , Ribonucleases/metabolism , Ribonucleases/genetics , Mice, Knockout , Transcription, Genetic , Cell Line, Tumor , NF-kappa B/metabolismABSTRACT
Lung infection during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via the angiotensin-I-converting enzyme 2 (ACE2) receptor induces a cytokine storm. However, the precise mechanisms involved in severe COVID-19 pneumonia are unknown. Here, we showed that interleukin-10 (IL-10) induced the expression of ACE2 in normal alveolar macrophages, causing them to become vectors for SARS-CoV-2. The inhibition of this system in hamster models attenuated SARS-CoV-2 pathogenicity. Genome-wide association and quantitative trait locus analyses identified a IFNAR2-IL10RB readthrough transcript, COVID-19 infectivity-enhancing dual receptor (CiDRE), which was highly expressed in patients harboring COVID-19 risk variants at the IFNAR2 locus. We showed that CiDRE exerted synergistic effects via the IL-10-ACE2 axis in alveolar macrophages and functioned as a decoy receptor for type I interferons. Collectively, our data show that high IL-10 and CiDRE expression are potential risk factors for severe COVID-19. Thus, IL-10R and CiDRE inhibitors might be useful COVID-19 therapies.
Subject(s)
COVID-19 , Humans , COVID-19/genetics , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , Interleukin-10/genetics , Macrophages, Alveolar/metabolism , Genome-Wide Association Study , Peptidyl-Dipeptidase A/metabolismABSTRACT
Regnase-1 and Roquin are RNA binding proteins essential for degradation of inflammation-related mRNAs and maintenance of immune homeostasis. However, their mechanistic relationship has yet to be clarified. Here, we show that, although Regnase-1 and Roquin regulate an overlapping set of mRNAs via a common stem-loop structure, they function in distinct subcellular locations: ribosome/endoplasmic reticulum and processing-body/stress granules, respectively. Moreover, Regnase-1 specifically cleaves and degrades translationally active mRNAs and requires the helicase activity of UPF1, similar to the decay mechanisms of nonsense mRNAs. In contrast, Roquin controls translationally inactive mRNAs, independent of UPF1. Defects in both Regnase-1 and Roquin lead to large increases in their target mRNAs, although Regnase-1 tends to control the early phase of inflammation when mRNAs are more actively translated. Our findings reveal that differential regulation of mRNAs by Regnase-1 and Roquin depends on their translation status and enables elaborate control of inflammation.
Subject(s)
Inflammation/metabolism , RNA Stability , RNA, Messenger/metabolism , Ribonucleases/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Base Sequence , Codon, Terminator , HeLa Cells , Humans , Inflammation/genetics , Inflammation/immunology , Mice , Molecular Sequence Data , NIH 3T3 Cells , Nucleic Acid Conformation , Polyribosomes/metabolism , Protein Biosynthesis , RNA, Messenger/chemistry , Ribosomal Proteins/metabolism , Trans-Activators/metabolismABSTRACT
The immune system has a critical role in orchestrating tissue healing. As a result, regenerative strategies that control immune components have proved effective1,2. This is particularly relevant when immune dysregulation that results from conditions such as diabetes or advanced age impairs tissue healing following injury2,3. Nociceptive sensory neurons have a crucial role as immunoregulators and exert both protective and harmful effects depending on the context4-12. However, how neuro-immune interactions affect tissue repair and regeneration following acute injury is unclear. Here we show that ablation of the NaV1.8 nociceptor impairs skin wound repair and muscle regeneration after acute tissue injury. Nociceptor endings grow into injured skin and muscle tissues and signal to immune cells through the neuropeptide calcitonin gene-related peptide (CGRP) during the healing process. CGRP acts via receptor activity-modifying protein 1 (RAMP1) on neutrophils, monocytes and macrophages to inhibit recruitment, accelerate death, enhance efferocytosis and polarize macrophages towards a pro-repair phenotype. The effects of CGRP on neutrophils and macrophages are mediated via thrombospondin-1 release and its subsequent autocrine and/or paracrine effects. In mice without nociceptors and diabetic mice with peripheral neuropathies, delivery of an engineered version of CGRP accelerated wound healing and promoted muscle regeneration. Harnessing neuro-immune interactions has potential to treat non-healing tissues in which dysregulated neuro-immune interactions impair tissue healing.
Subject(s)
Calcitonin Gene-Related Peptide , Macrophages , Neutrophils , Nociceptors , Wound Healing , Animals , Mice , Autocrine Communication , Calcitonin Gene-Related Peptide/metabolism , Calcitonin Gene-Related Peptide/pharmacology , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Efferocytosis , Macrophages/cytology , Macrophages/metabolism , Monocytes/cytology , Monocytes/metabolism , Muscle, Skeletal , NAV1.8 Voltage-Gated Sodium Channel/deficiency , NAV1.8 Voltage-Gated Sodium Channel/genetics , NAV1.8 Voltage-Gated Sodium Channel/metabolism , Neutrophils/cytology , Neutrophils/metabolism , Nociceptors/metabolism , Paracrine Communication , Peripheral Nervous System Diseases/complications , Receptor Activity-Modifying Protein 1/metabolism , Regeneration/drug effects , Skin , Thrombospondin 1/metabolism , Wound Healing/drug effects , Wound Healing/immunology , Humans , Male , FemaleABSTRACT
Mammalian autophagy-related 8 (Atg8) homologs consist of LC3 proteins and GABARAPs, all of which are known to be involved in canonical autophagy. In contrast, the roles of Atg8 homologs in noncanonical autophagic processes are not fully understood. Here we show a unique role of GABARAPs, in particular gamma-aminobutyric acid (GABA)-A-receptor-associated protein-like 2 (Gabarapl2; also known as Gate-16), in interferon-γ (IFN-γ)-mediated antimicrobial responses. Cells that lacked GABARAPs but not LC3 proteins and mice that lacked Gate-16 alone were defective in the IFN-γ-induced clearance of vacuolar pathogens such as Toxoplasma. Gate-16 but not LC3b specifically associated with the small GTPase ADP-ribosylation factor 1 (Arf1) to mediate uniform distribution of interferon-inducible GTPases. The lack of GABARAPs reduced Arf1 activation, which led to formation of interferon-inducible GTPase-containing aggregates and hampered recruitment of interferon-inducible GTPases to vacuolar pathogens. Thus, GABARAPs are uniquely required for antimicrobial host defense through cytosolic distribution of interferon-inducible GTPases.
Subject(s)
ADP-Ribosylation Factor 1/immunology , Autophagy/immunology , Carrier Proteins/immunology , Interferon-gamma/immunology , Microtubule-Associated Proteins/immunology , Toxoplasma/immunology , Toxoplasmosis/immunology , ADP-Ribosylation Factor 1/metabolism , Animals , Apoptosis Regulatory Proteins , Autophagy-Related Protein 8 Family , CRISPR-Cas Systems , Carrier Proteins/metabolism , Computer Simulation , Cytoskeletal Proteins/immunology , Cytoskeletal Proteins/metabolism , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Fluorescent Antibody Technique , GTP Phosphohydrolases/immunology , GTP Phosphohydrolases/metabolism , Gene Editing , Immunoblotting , Immunoprecipitation , Interferon-gamma/metabolism , Intracellular Signaling Peptides and Proteins , Membrane Proteins/immunology , Membrane Proteins/metabolism , Mice , Microtubule-Associated Proteins/metabolismABSTRACT
Fibrosis is an incurable disorder of unknown etiology. Segregated-nucleus-containing atypical monocytes (SatMs) are critical for the development of fibrosis. Here we examined the mechanisms that recruit SatMs to pre-fibrotic areas. A screen based on cytokine expression in the fibrotic lung revealed that the chemokine Cxcl12, which is produced by apoptotic nonhematopoietic cells, was essential for SatM recruitment. Analyses of lung tissues at fibrosis onset showed increased expression of Rbm7, a component of the nuclear exosome targeting complex. Rbm7 deletion suppressed bleomycin-induced fibrosis and at a cellular level, suppressed apoptosis of nonhematopoietic cells. Mechanistically, Rbm7 bound to noncoding (nc)RNAs that form subnuclear bodies, including Neat1 speckles. Dysregulated expression of Rbm7 resulted in the nuclear degradation of Neat1 speckles, the dispersion of the DNA repair protein BRCA1, and the triggering of apoptosis. Thus, Rbm7 in epithelial cells plays a critical role in the development of fibrosis by regulating ncRNA decay and thereby the production of chemokines that recruit SatMs.
Subject(s)
Apoptosis/immunology , Cell Nucleus/immunology , Exosomes/immunology , Pulmonary Fibrosis/immunology , RNA-Binding Proteins/immunology , Animals , Apoptosis/genetics , Cell Nucleus/genetics , Cell Nucleus/metabolism , Chemokine CXCL12/immunology , Chemokine CXCL12/metabolism , Exosomes/genetics , Exosomes/metabolism , Gene Expression Regulation/immunology , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Monocytes/immunology , Monocytes/metabolism , NIH 3T3 Cells , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolismABSTRACT
Regnase-1 (also known as Zc3h12a and MCPIP1) is an RNase that destabilizes a set of mRNAs, including Il6 and Il12b, through cleavage of their 3' UTRs. Although Regnase-1 inactivation leads to development of an autoimmune disease characterized by T cell activation and hyperimmunoglobulinemia in mice, the mechanism of Regnase-1-mediated immune regulation has remained unclear. We show that Regnase-1 is essential for preventing aberrant effector CD4(+) T cell generation cell autonomously. Moreover, in T cells, Regnase-1 regulates the mRNAs of a set of genes, including c-Rel, Ox40, and Il2, through cleavage of their 3' UTRs. Interestingly, T cell receptor (TCR) stimulation leads to cleavage of Regnase-1 at R111 by Malt1/paracaspase, freeing T cells from Regnase-1-mediated suppression. Furthermore, Malt1 protease activity is critical for controlling the mRNA stability of T cell effector genes. Collectively, these results indicate that dynamic control of Regnase-1 expression in T cells is critical for controlling T cell activation.
Subject(s)
Caspases/metabolism , Lymphocyte Activation , Neoplasm Proteins/metabolism , Ribonucleases/metabolism , T-Lymphocytes, Helper-Inducer/immunology , Animals , Autoimmune Diseases/immunology , Humans , Interleukin-2/genetics , Jurkat Cells , Membrane Glycoproteins/genetics , Mice , Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein , OX40 Ligand , Proto-Oncogene Proteins c-rel/genetics , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes, Helper-Inducer/metabolism , Tumor Necrosis Factors/geneticsABSTRACT
Tight regulation of Toll-like receptor (TLR)-mediated inflammatory responses is important for innate immunity. Here, we show that T-cell death-associated gene 51 (TDAG51/PHLDA1) is a novel regulator of the transcription factor FoxO1, regulating inflammatory mediator production in the lipopolysaccharide (LPS)-induced inflammatory response. TDAG51 induction by LPS stimulation was mediated by the TLR2/4 signaling pathway in bone marrow-derived macrophages (BMMs). LPS-induced inflammatory mediator production was significantly decreased in TDAG51-deficient BMMs. In TDAG51-deficient mice, LPS- or pathogenic Escherichia coli infection-induced lethal shock was reduced by decreasing serum proinflammatory cytokine levels. The recruitment of 14-3-3ζ to FoxO1 was competitively inhibited by the TDAG51-FoxO1 interaction, leading to blockade of FoxO1 cytoplasmic translocation and thereby strengthening FoxO1 nuclear accumulation. TDAG51/FoxO1 double-deficient BMMs showed significantly reduced inflammatory mediator production compared with TDAG51- or FoxO1-deficient BMMs. TDAG51/FoxO1 double deficiency protected mice against LPS- or pathogenic E. coli infection-induced lethal shock by weakening the systemic inflammatory response. Thus, these results indicate that TDAG51 acts as a regulator of the transcription factor FoxO1, leading to strengthened FoxO1 activity in the LPS-induced inflammatory response.
Subject(s)
Escherichia coli , Lipopolysaccharides , Mice , Animals , 14-3-3 Proteins , Transcription Factors/genetics , Inflammation MediatorsABSTRACT
Mitochondrial DNA (mtDNA) leakage into the cytoplasm can occur when cells are exposed to noxious stimuli. Specific sensors recognize cytoplasmic mtDNA to promote cytokine production. Cytoplasmic mtDNA can also be secreted extracellularly, leading to sterile inflammation. However, the mode of secretion of mtDNA out of cells upon noxious stimuli and its relevance to human disease remain unclear. Here, we show that pyroptotic cells secrete mtDNA encapsulated within exosomes. Activation of caspase-1 leads to mtDNA leakage from the mitochondria into the cytoplasm via gasdermin-D. Caspase-1 also induces intraluminal membrane vesicle formation, allowing for cellular mtDNA to be taken up and secreted as exosomes. Encapsulation of mtDNA within exosomes promotes a strong inflammatory response that is ameliorated upon exosome biosynthesis inhibition in vivo. We further show that monocytes derived from patients with Behçet's syndrome (BS), a chronic systemic inflammatory disorder, show enhanced caspase-1 activation, leading to exosome-mediated mtDNA secretion and similar inflammation pathology as seen in BS patients. Collectively, our findings support that mtDNA-containing exosomes promote inflammation, providing new insights into the propagation and exacerbation of inflammation in human inflammatory diseases.
Subject(s)
Behcet Syndrome , Exosomes , Humans , DNA, Mitochondrial/genetics , DNA, Mitochondrial/metabolism , Behcet Syndrome/genetics , Behcet Syndrome/metabolism , Exosomes/genetics , Mitochondria/genetics , Inflammation/metabolism , Caspases/metabolismABSTRACT
NLRP3 forms an inflammasome with its adaptor ASC, and its excessive activation can cause inflammatory diseases. However, little is known about the mechanisms that control assembly of the inflammasome complex. Here we show that microtubules mediated assembly of the NLRP3 inflammasome. Inducers of the NLRP3 inflammasome caused aberrant mitochondrial homeostasis to diminish the concentration of the coenzyme NAD(+), which in turn inactivated the NAD(+)-dependent α-tubulin deacetylase sirtuin 2; this resulted in the accumulation of acetylated α-tubulin. Acetylated α-tubulin mediated the dynein-dependent transport of mitochondria and subsequent apposition of ASC on mitochondria to NLRP3 on the endoplasmic reticulum. Therefore, in addition to direct activation of NLRP3, the creation of optimal sites for signal transduction by microtubules is required for activation of the entire NLRP3 inflammasome.
Subject(s)
Carrier Proteins/metabolism , Cytoskeletal Proteins/metabolism , Endoplasmic Reticulum/metabolism , Inflammasomes/metabolism , Mitochondria/physiology , Acetylation , Animals , Apoptosis Regulatory Proteins , CARD Signaling Adaptor Proteins , Carrier Proteins/immunology , Cell Line , Cytoplasmic Streaming , Cytoskeletal Proteins/genetics , Dyneins/metabolism , Female , Mice , Mice, Inbred C57BL , Microtubules/metabolism , NAD/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein , Signal Transduction , Sirtuin 2/metabolism , Tubulin/chemistry , Tubulin/metabolismABSTRACT
Regnase-1 is an RNase that plays a critical role in negatively regulating immune responses by destabilizing inflammatory mRNAs. Dysfunction of Regnase-1 can be a major cause of various inflammatory diseases with tissue injury and immune cell infiltration into organs. This study focuses on the role of RNase activity of Regnase-1 in developing inflammatory diseases. We have constructed mice with a single point mutation at the catalytic center of Regnase-1 RNase domain, which lacks endonuclease activity. D141N mutant mice demonstrated systemic inflammation, immune cell infiltration into various organs and progressive development of lung granuloma. CD4+ T cells, mainly affected by this mutation, upregulated mTORC1 pathway and facilitated the autoimmune trait in D141N mutation. Moreover, serine/threonine kinase Pim2 contributed to lung inflammation in this mutation. Inhibition of Pim2 kinase activity ameliorated granulomatous inflammation, immune cell infiltration and proliferation in the lungs. Additionally, Pim2 inhibition reduced the expression of adhesion molecules on CD4+ T cells, suggesting a role for Pim2 in facilitating leukocyte adhesion and migration to inflamed tissues. Our findings provide new insights into the role of Regnase-1 RNase activity in controlling immune function and underscore the therapeutic relevance of targeting Pim2 to modulate abnormal immune responses.
ABSTRACT
Transforming growth factor-ß-activated kinase 1 (TAK1) plays a pivotal role in innate and adaptive immunity. TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB pathways downstream of diverse immune receptors, including toll-like receptors (TLRs). Upon stimulation with TLR ligands, TAK1 is activated via recruitment to the lysine 63-linked polyubiquitin chain through TAK1-binding protein 2 (TAB2) and TAB3. However, the physiological importance of TAB2 and TAB3 in macrophages is still controversial. A previous study has shown that mouse bone marrow-derived macrophages (BMDMs) isolated from mice double deficient for TAB2 and TAB3 produced tumor necrosis factor (TNF)-α and interleukin (IL)-6 to the similar levels as control wild-type BMDMs in response to TLR ligands such as lipopolysaccharide (LPS) or Pam3CSK4, indicating that TAB2 and TAB3 are dispensable for TLR signaling. In this study, we revisited the role of TAB2 and TAB3 using an improved mouse model. We observed a significant impairment in the production of pro-inflammatory cytokines and chemokine in LPS- or Pam3CSK4-treated BMDMs deficient for both TAB2 and TAB3. Double deficiency of TAB2 and TAB3 resulted in the decreased activation of NF-κB and MAPK pathways as well as the slight decrease in TAK1 activation in response to LPS or Pam3CSK4. Notably, the TLR-mediated expression of inhibitor of NF-κB (IκB)ζ was severely compromised at the protein and messenger RNA (mRNA) levels in the TAB2/TAB3 double-deficient BMDMs, thereby impeding IL-6 production. Our results suggest that TAB2 and TAB3 play a redundant and indispensable role in the TLR signaling pathway.
Subject(s)
Adaptor Proteins, Signal Transducing , Cytokines , Macrophages , Mice, Inbred C57BL , Mice, Knockout , Toll-Like Receptors , Animals , Mice , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Macrophages/immunology , Macrophages/metabolism , Toll-Like Receptors/metabolism , Cytokines/metabolism , Signal Transduction/immunology , NF-kappa B/metabolism , MAP Kinase Kinase Kinases/metabolism , MAP Kinase Kinase Kinases/immunology , MAP Kinase Kinase Kinases/genetics , Cells, CulturedABSTRACT
TLRs play central roles in host defense. In this issue of Immunity, Zhang et al. (2016) generate structures of TLR7 bound to multiple ligands and provide insight into the mechanism of TLR7 ligand recognition that highlights the differences in the features of the TLR subfamily.
Subject(s)
Toll-Like Receptor 7/chemistry , Toll-Like Receptor 7/metabolism , Animals , Immunity/immunology , Ligands , RNA/metabolism , Toll-Like Receptor 7/immunologyABSTRACT
Sepsis is a host inflammatory response to severe infection associated with high mortality that is caused by lymphopenia-associated immunodeficiency. However, it is unknown how lymphopenia persists after the accelerated lymphocyte apoptosis subsides. Here we show that sepsis rapidly ablated osteoblasts, which reduced the number of common lymphoid progenitors (CLPs). Osteoblast ablation or inducible deletion of interleukin-7 (IL-7) in osteoblasts recapitulated the lymphopenic phenotype together with a lower CLP number without affecting hematopoietic stem cells (HSCs). Pharmacological activation of osteoblasts improved sepsis-induced lymphopenia. This study demonstrates a reciprocal interaction between the immune and bone systems, in which acute inflammation induces a defect in bone cells resulting in lymphopenia-associated immunodeficiency, indicating that bone cells comprise a therapeutic target in certain life-threatening immune reactions.
Subject(s)
B-Lymphocytes/physiology , Immunologic Deficiency Syndromes/immunology , Interleukin-7/metabolism , Lymphoid Progenitor Cells/physiology , Osteoblasts/physiology , Sepsis/immunology , T-Lymphocytes/physiology , Animals , Cells, Cultured , Cytokines/metabolism , Interleukin-7/genetics , Lymphocyte Depletion , Lymphopenia , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
Infection of cells by microorganisms activates the inflammatory response. The initial sensing of infection is mediated by innate pattern recognition receptors (PRRs), which include Toll-like receptors, RIG-I-like receptors, NOD-like receptors, and C-type lectin receptors. The intracellular signaling cascades triggered by these PRRs lead to transcriptional expression of inflammatory mediators that coordinate the elimination of pathogens and infected cells. However, aberrant activation of this system leads to immunodeficiency, septic shock, or induction of autoimmunity. In this Review, we discuss the role of PRRs, their signaling pathways, and how they control inflammatory responses.
Subject(s)
Inflammation/immunology , Receptors, Pattern Recognition/immunology , Animals , Cytoplasm/genetics , Humans , Infections/immunology , Toll-Like Receptors/immunologyABSTRACT
Meiosis is a hallmark event in germ cell development that accompanies sequential events executed by numerous molecules. Therefore, characterization of these factors is one of the best strategies to clarify the mechanism of meiosis. Here, we report tripartite motif-containing 41 (TRIM41), a ubiquitin ligase E3, as an essential factor for proper meiotic progression and fertility in male mice. Trim41 knockout (KO) spermatocytes exhibited synaptonemal complex protein 3 (SYCP3) overloading, especially on the X chromosome. Furthermore, mutant mice lacking the RING domain of TRIM41, required for the ubiquitin ligase E3 activity, phenocopied Trim41 KO mice. We then examined the behavior of mutant TRIM41 (ΔRING-TRIM41) and found that ΔRING-TRIM41 accumulated on the chromosome axes with overloaded SYCP3. This result suggested that TRIM41 exerts its function on the chromosome axes. Our study revealed that Trim41 is essential for preventing SYCP3 overloading, suggesting a TRIM41-mediated mechanism for regulating chromosome axis protein dynamics during male meiotic progression.
Subject(s)
Nuclear Proteins , Synaptonemal Complex , Ubiquitin-Protein Ligases/metabolism , Animals , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Male , Meiosis/genetics , Mice , Mice, Knockout , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Spermatocytes/metabolism , Synaptonemal Complex/genetics , Synaptonemal Complex/metabolism , Ubiquitin-Protein Ligases/geneticsABSTRACT
The RNA-binding protein (RBP) Regnase-1 is an endonuclease that regulates immune responses by modulating target mRNA stability. Regnase-1 degrades a group of inflammation-associated mRNAs, which contributes to a balanced immune response and helps prevent autoimmune diseases. Regnase-1 also cleaves its own mRNA by binding stem-loop (SL) RNA structures in its 3'UTR. To understand how this autoregulation is important for immune responses, we generated mice with a 2-bp genome deletion in the target SL of the Regnase-1 3'-untranslated region (3'UTR). Deletion of these nucleotides inhibited SL formation and limited Regnase-1-mediated mRNA degradation. Mutant mice had normal hematopoietic cell differentiation. Biochemically, mutation of the 3'UTR SL increased Regnase-1 mRNA stability and enhanced both Regnase-1 mRNA and protein levels in mouse embryonic fibroblasts (MEFs). The expression of Il6, a Regnase-1 target gene, was constitutively suppressed at steady-state in mutant MEFs. Additionally, Regnase-1 protein expression in mutant MEFs was significantly elevated compared to that in wild-type MEFs at steady state and upon proinflammatory cytokine stimulation. These data suggest a negative feedback mechanism for Regnase-1 expression and represent a unique mouse model to probe Regnase-1 overexpression in vivo.
Subject(s)
Ribonucleases , Self-Control , Animals , Mice , Ribonucleases/genetics , 3' Untranslated Regions/genetics , Fibroblasts/metabolism , Inflammation/geneticsABSTRACT
The maintenance of immune homeostasis requires regulatory T cells (Treg cells). Here we found that Treg cellspecific ablation of Ubc13, a Lys63 (K63)-specific ubiquitin-conjugating enzyme, caused aberrant T cell activation and autoimmunity. Although Ubc13 deficiency did not affect the survival of Treg cells or expression of the transcription factor Foxp3, it impaired the in vivo suppressive function of Treg cells and rendered them sensitive to the acquisition of T helper type 1 (TH1) cell and interleukin 17 (IL-17)-producing helper T (TH17) celllike effector phenotypes. This function of Ubc13 involved its downstream target, the kinase IKK. The Ubc13-IKK signaling axis controlled the expression of specific Treg cell effector molecules, including IL-10 and SOCS1. Collectively, our findings suggest that the Ubc13-IKK signaling axis regulates the molecular program that maintains Treg cell function and prevents Treg cells from acquiring inflammatory phenotypes.