Toxoplasma gondii is an obligate intracellular parasite that stimulates production of high levels of proinflammatory cytokines, which are important for innate immunity. NLRs, i.e., nucleotide-binding oligomerization domain (NOD)-like receptors, play a crucial role as innate immune sensors and form multiprotein complexes called inflammasomes, which mediate caspase-1-dependent processing of pro-IL-1β. To elucidate the role of inflammasome components in T. gondii-infected THP-1 macrophages, we examined inflammasome-related gene expression and mechanisms of inflammasome-regulated cytokine IL-1β secretion. The results revealed a significant upregulation of IL-1β after T. gondii infection. T. gondii infection also upregulated the expression of inflammasome sensors, including NLRP1, NLRP3, NLRC4, NLRP6, NLRP8, NLRP13, AIM2, and NAIP, in a time-dependent manner. The infection also upregulated inflammasome adaptor protein ASC and caspase-1 mRNA levels. From this study, we newly found that T. gondii infection regulates NLRC4, NLRP6, NLRP8, NLRP13, AIM2, and neuronal apoptosis inhibitor protein (NAIP) gene expressions in THP-1 macrophages and that the role of the inflammasome-related genes may be critical for mediating the innate immune responses to T. gondii infection.
Apoptosis ; Cytokines ; Gene Expression ; Immunity, Innate ; Inflammasomes* ; Macrophages* ; Multiprotein Complexes ; Negotiating ; Neurons ; Parasites ; RNA, Messenger ; Toxoplasma* ; Up-Regulation

Inflammasomes are cytosolic multiprotein complexes that sense microbial motifs or cellular stress and stimulate caspase-1-dependent cytokine secretion and cell death. Recently, it has become increasingly evident that both DNA and RNA viruses activate inflammasomes, which control innate and adaptive immune responses against viral infections. In addition, recent studies suggest that certain microbiota induce inflammasomes-dependent adaptive immunity against influenza virus infections. Here, we review recent advances in research into the role of inflammasomes in antiviral immunity.
Adaptive Immunity ; Cell Death ; Cytosol ; Dendritic Cells ; DNA ; Inflammasomes* ; Influenza Vaccines* ; Influenza, Human* ; Metagenome ; Microbiota ; Multiprotein Complexes ; Orthomyxoviridae ; RNA Viruses

The inflammasome is a group of multiprotein complexes in the cytoplasm, which can activate caspase-1 that mediates the maturation and release of IL-1β, IL-18, IL-33 and other pro-inflammatory cytokines.NALP1 (NACHT leucine-rich-repeat protein 1), also known as NLRP1, is the first one of the identified complex inflammasomes with definite ligands mainly involved in the activation of inflammasome assembly and the formation of apoptotic bodies. Moreover, it was also found that NLRP1 plays an important biological role in the development of acute leukemia, the bone marrow hematopoietic stem cell apoptosis and other blood diseases. This review briefly summarizes the structure, activation mechanism, regulation and the role of NLRP1 in the hematopoietic system.
Adaptor Proteins, Signal Transducing ; metabolism ; Apoptosis ; Apoptosis Regulatory Proteins ; metabolism ; Cytokines ; Hematologic Diseases ; metabolism ; pathology ; Humans ; Inflammasomes ; Multiprotein Complexes

Inflammasomes are intracellular multiprotein complexes that coordinate anti-pathogenic host defense during inflammatory responses in myeloid cells, especially macrophages. Inflammasome activation leads to activation of caspase-1, resulting in the induction of pyroptosis and the secretion of pro-inflammatory cytokines including interleukin (IL)-1β and IL-18. Although the inflammatory response is an innate host defense mechanism, chronic inflammation is the main cause of rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), and Sjögren's syndrome (SS). Since rheumatic diseases are inflammatory/autoimmune disorders, it is reasonable to hypothesize that inflammasomes activated during the inflammatory response play a pivotal role in development and progression of these diseases. Indeed, previous studies have provided important observations that inflammasomes are actively involved in the pathogenesis of inflammatory/autoimmune rheumatic diseases. In this review, we summarize the current knowledge on several types of inflammasomes during macrophage-mediated inflammatory responses and discuss recent research regarding the role of inflammasomes in the pathogenesis of inflammatory/autoimmune rheumatic diseases. This avenue of research could provide new insights for the development of promising therapeutics to treat inflammatory/autoimmune rheumatic diseases.
Arthritis, Rheumatoid ; Autoimmunity ; Cytokines ; Inflammasomes* ; Inflammation ; Interleukin-18 ; Interleukins ; Lupus Erythematosus, Systemic ; Macrophages ; Multiprotein Complexes ; Myeloid Cells ; Pyroptosis ; Rheumatic Diseases* ; Spondylitis, Ankylosing

Amino acids are fundamental nutrients for protein synthesis and cell growth (increase in cell size). Recently, many compelling evidences have shown that the level of amino acids is sensed by extra- or intra-cellular amino acids sensor(s) and regulates protein synthesis/degradation. Mammalian target of rapamycin complex 1 (mTORC1) is placed in a central position in cell growth regulation and dysregulation of mTOR signaling pathway has been implicated in many serious human diseases including cancer, diabetes, and tissue hypertrophy. Although amino acids are the most potent activator of mTORC1, how amino acids activate mTOR signaling pathway is still largely unknown. This is partly because of the diversity of amino acids themselves including structure and metabolism. In this review, current proposed amino acid sensing mechanisms to regulate mTORC1 and the evidences pro/against the proposed models are discussed.
Amino Acids ; Humans ; Hypertrophy ; Multiprotein Complexes ; Sirolimus ; TOR Serine-Threonine Kinases

Mammalian target of rapamycin complex (mTORC) is an important center for regulating cellular growth, survival and metabolism. mTORC plays a vital role in maintenance of normal physiological activities and homeostasis in organism. According to protein components, mTORC can be divided into two distinct protein complexes: mTORC1 and mTORC2. The main protein components of mTORC2 include mTOR, Rictor, mLST8, Deptor, mSin1, Protor and Hsp70. By means of activating AKT, PKCα, SGK1 and so on, the mTORC regulates many vital activities:embryonic development, cytoskeletal reconstitution,cell migration and protein post-translational modification. The abnormality of mTORC2 signaling pathway has been confirmed to be associated with tumorigenesis, therefore, further understanding the components, functions and signalling pathway of mTORC2 will provide a new insights in developing targeted cancer therapy. In this review, the structure and signalling pathway of mTORC2 and its roles in hematological malignancies are discussed and summarised.
Animals ; Hematologic Neoplasms ; Humans ; Mechanistic Target of Rapamycin Complex 2 ; Multiprotein Complexes ; Signal Transduction ; TOR Serine-Threonine Kinases

The CCR4-NOT complex is a highly conserved, multifunctional machinery controlling mRNA metabolism. Its components have been implicated in several aspects of mRNA and protein expression, including transcription initiation, elongation, mRNA degradation, ubiquitination, and protein modification. In this review, we will focus on the role of the CCR4-NOT complex in mRNA degradation. The complex contains two types of deadenylase enzymes, one belonging to the DEDD-type family and one belonging to the EEP-type family, which shorten the poly(A) tails of mRNA. We will review the present state of structure-function analyses into the CCR4-NOT deadenylases and summarize current understanding of their roles in mRNA degradation. We will also review structural and functional work on the Tob/BTG family of proteins, which are known to interact with the CCR4-NOT complex and which have been reported to suppress deadenylase activity in vitro.
Animals ; Humans ; Multiprotein Complexes ; chemistry ; genetics ; metabolism ; Protein Conformation ; RNA, Messenger ; genetics ; metabolism ; Transcription Factors ; chemistry ; genetics ; metabolism

BACKGROUND: Mitochondrial dysfunction plays an important role in Abeta-induced neuronal toxicity in Alzheimer's disease (AD). We measured the membrane potentials of mitochondria (delta psim) and assessed the genetic expressions of A beta(25-35)-induced neurotoxicity in the human neuroblastoma cell line, SK-N-SH cell. METHODS: SK-N-SH cells were incubated with a single dose of 25 micrometer A beta(25-35) for 0-24 hours, and kinetic study was done. delta psim was measured by flow cytometry. Messenger RNA expressions of cytochrome c oxidase (COX), cytochrome c, succinate dehydrogenase (SDH), amyloid-beta alcohol dehydrogenase (ABAD), caspase 9, and Bcl-2 were measured by quantitative real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR). Cell death rate was measured by MTT reduction assay. RESULTS: delta psim was reduced at 24 hours. mRNA expression for COX gradually decreased by about 29% (p<0.05) while-expressions for cytochrome c, SDH, ABAD, and caspase 9 increased (p<0.05) progressively during the 24-hour time period. Bcl-2 expression decreased (p<0.05) gradually; and apoptotic cell death rate was about 24% (p<0.01) by 24 hours. CONCLUSION: Extracellular administration of A beta(25-35) contributes directly to mitochondrial dysfunction in SK-N-SH cells with the enzymatic impairment of the tricarboxylic acid cycle and electron transport chain, and eventually leading to apoptotic cell death.
Alcohol Dehydrogenase ; Alzheimer Disease ; Amyloid beta-Peptides ; Apoptosis ; Caspase 9 ; Cell Death ; Cell Line ; Citric Acid Cycle ; Cytochromes c ; Electron Transport ; Electron Transport Complex IV ; Flow Cytometry ; Gene Expression ; Humans ; Membrane Potentials ; Mitochondria ; Neuroblastoma ; Neurons ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger ; Succinate Dehydrogenase

The target of rapamycin (TOR) signaling pathway conserved from yeast to human plays critical roles in regulation of eukaryotic cell growth. It has been shown that TOR pathway is involved in several cellular processes, including ribosome biogenesis, nutrient response, autophagy and aging. However, due to the functional diversity of TOR pathway, we do not know yet some key effectors of the pathway. To find unknown effectors of TOR signaling pathway, we took advantage of a green fluorescent protein (GFP)-tagged collection of budding yeast Saccharomyces cerevisiae . We analyzed protein abundance changes by measuring the GFP fluorescence intensity of 4156 GFP-tagged yeast strains under inhibition of TOR pathway. Our proteomic analysis argues that 83 proteins are decreased whereas 32 proteins are increased by treatment of rapamycin, a specific inhibitor of TOR complex 1 (TORC1). We found that, among the 115 proteins that show significant changes in protein abundance under rapamycin treatment, 37 proteins also show expression changes in the mRNA levels by more than 2-fold under the same condition. We suggest that the 115 proteins indentified in this study may be directly or indirectly involved in TOR signaling and can serve as candidates for further investigation of the effectors of TOR pathway.
Aging ; Autophagy ; Eukaryotic Cells ; Fluorescence ; Humans ; Imidazoles ; Multiprotein Complexes ; Nitro Compounds ; Proteins ; Proteome ; Ribosomes ; RNA, Messenger ; Saccharomyces cerevisiae ; Saccharomycetales ; Sirolimus ; TOR Serine-Threonine Kinases ; Yeasts ; Organelle Biogenesis

OBJECTIVETo investigate the expression of CSN complex (COP9 signal some subunits) in the patients with acute promyelocytic leukemia (APL) and its significance in the ATRA-induced APL differentiation.

METHODSUsing the NB4 cells as a model, morphologic observation and myeloid differentiation marker CD11b detection were used to monitor ATRA-induced APL differentiation, the expression of CSN complex in cell differentiation was detected by Western blot and reverse transcription real time fluorescent quantitative PCR (RT-qPCR) method. RT-qPCR was also used to detect the relative expression level of COP9 signalosome subunits in the APL patients and remission after treatment.

RESULTSATRA could obviously enhance CD11b expression; the cell morphology showed obvious differentiation characteristics. During the differentiation, the expression of COP9 signalosome subunits was down-regulated by ATRA. Meanwhile, the CSN expression level in newly diagnosed APL patients was much higher than that in controls (non-leukemia) (P < 0.05). The level of CSN expression was obviously down-regulated when APL patients achieved complete remission.

CONCLUSIONThe high CSN expression level in APL patients can be down-regulated by ATRA. CSN complex may have a significant effect on the pathogenesis and therapy of APL.

COP9 Signalosome Complex ; Cell Differentiation ; Cell Line, Tumor ; Down-Regulation ; Humans ; Leukemia, Promyelocytic, Acute ; metabolism ; Multiprotein Complexes ; metabolism ; Peptide Hydrolases ; metabolism ; Tretinoin ; pharmacology