DOCSLIB.ORG

The NOD: a Signaling Module That Regulates Apoptosis and Host Defense Against Pathogens

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The NOD: a Signaling Module That Regulates Apoptosis and Host Defense Against Pathogens Oncogene (2001) 20, 6473 ± 6481 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc The NOD: a signaling module that regulates apoptosis and host defense against pathogens Naohiro Inohara1 and Gabriel NunÄ ez*,1 1Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, Michigan, MI 48109, USA Nods, a growing family of proteins containing a molecule that induces systemic acquired resistance nucleotide-binding oligomerization domain (NOD), are (SAR) (Feys and Parker, 2000). In higher multicellular involved in the regulation of programmed cell death organisms, appropriate development and tissue home- (PCD) and immune responses. Members of the family ostasis require highly regulated activation of PCD. include Apaf-1, Ced-4, Nod1, Nod2, and the cytosolic Whereas PCD induced during the defense against products of plant disease resistance genes. The NOD pathogens in both animal and plants is accompanied module is homologous to the ATP-binding cassette by the production of pro-in¯ammatory molecules, that (ABC) found in a large number of proteins with diverse associated with tissue development and homeostasis is biological function. The centrally located NOD promotes devoid of an in¯ammatory response (Jacobson et al., activation of eector molecules through self-association 1997; Feys and Parker, 2000). Despite these dierences, and induced proximity of binding partners. The C- both types of PCD are associated with the induction of terminal domain of Nods serves as a sensor for similar morphological features including membrane intracellular ligands, whereas the N-terminal domain blebbing, cytosolic fragmentation, nuclear condensa- mediates binding to dowstream eector molecules and tion and fragmentation as well as biochemical events activation of diverse signaling pathways. Thus, Nods such as degradation of genomic DNA, proteolysis and activate, through the NOD module, diverse signaling redistribution of membrane lipids (Kerr et al., 1972; pathways involved in the elimination of cells via PCD Wyllie, 1980). These changes associated with PCD, and the host defense against pathogens. Oncogene generally referred as apoptosis, are largely due to the (2001) 20, 6473 ± 6481. activation of caspases, a family of cysteine proteases (NuÂnÄ ez et al., 1998; Kumar, 1999). Mammalian cells Keywords: apoptosis; Apaf-1/Nod1/CED4 family; pro- have more than 14 caspases and synthesize them as grammed cell death; ATPase/GTPases; NOD domain enzymatically inactive forms. Once an apical caspase such as caspase-8 or caspase-9 is activated, the protease activates downstream (eector) caspases and non- caspase proteases causing massive proteolytic activity in the cytosol and the orderly demise of the cell Introduction (Kumar, 1999). Therefore, activation of apical caspases is a critical step in that it determines cell fate and as Programmed cell death (PCD) or apoptosis plays a such is strictly regulated by speci®c regulatory critical role not only during embryonic development molecules. and cellular homeostasis in the adult, but also in the clearance of invading pathogens by host tissues (Weinrauch and Zychlinsky, 1999). Multicellular Ced-4 and Apaf-1 contain a NOD domain that is critical organisms have several host defense systems to prevent for functional activity proliferation and propagation of invading pathogens. One of the most ancient types of immune reactions is Early genetic studies in the nematode Caenorhabditis the elimination of pathogen infected cells by PCD elegans revealed molecules which play critical roles in (Weinrauch and Zychlinsky, 1999). In addition, the induction, regulation and execution of PCD during infected host cells produce defensins and pro-in¯am- worm development. Ced-3 and Ced-4 are required for matory cytokines that play an important role in the the execution step of PCD, whereas Ced-9 protects clearance of the invading pathogen. In plants, patho- cells from PCD during normal development (Ellis and gens trigger a specialized form of PCD known as the Horvitz, 1986; Metzstein et al., 1998). Homology hypersensitive response (HR) and the production of analysis and functional assays demonstrated that defensins and salicylic acid, a phenolic signaling Ced-3 is a caspase, Ced-4 is the activator of Ced-3 and Ced-9 is a pro-survival member of the Bcl-2 family (Yuan and Horvitz, 1992; Yuan et al., 1993; *Correspondence: G NunÄ ez; E-mail: [email protected] Hengartner and Horvitz, 1994; Chinnaiyan et al., Proteins containing nucleotide-binding oligomerization domains N Inohara and G NunÄez 6474 1997a). Both Ced-3 and Ced-4 have N-terminal Ced-4 and Apaf-1 activate target caspases through caspase-recruitment domains (CARDs) that associate induced proximity with each other through homophilic interaction between their CARDs (Hofmann et al., 1997; Wu et The structural similarity between Ced-4 and Apaf-1 al., 1997a; Irmler et al., 1997; Seshagiri et al., 1998). re¯ects the fact that both molecules use a common Ced-4 has an additional module, the nucleotide-binding mechanism to activate their target caspases. The N- domain (NBD), which is essential for Ced-3 activation terminal CARD of each protein mediates interaction (Chinnaiyan et al., 1997b; Chaudhary et al., 1998). with that of the target caspase, whereas the NOD self- Biochemical approaches to identify cytosolic factors associates and oligomerizes (Figure 1a). Through their that activate human caspase-3, an eector caspase, NODs and CARDs, Apaf-1 and presumably Ced-4 revealed a cell death machinery in mammals similar form a large protein complex containing oligomerized to that identi®ed by genetic studies in C. elegans. Apaf-1/Ced-4 bound to caspase-9 or Ced-3, respec- Puri®cation of caspase-3 activators and functional tively, which allows proximity and enzymatic self- reconstitution assays revealed caspase-9 as a direct activation of the bound caspases (Yang et al., 1998; Hu activator of caspase-3 (Zou et al., 1997). Apaf-1 was et al., 1998a; Srinivasula et al., 1998; Salvesen and identi®ed as the activator of caspase-9, a step that Dixit, 1999). The mechanism by which these caspases requires dATP/ATP and cytochrome c, a ligand for are activated by Ced-4 and Apaf-1 appears to be Apaf-1 released from damaged mitochondria (Li et similar to that proposed for activation of caspase-8 in al., 1997). Sequence analysis revealed that Apaf-1 is the death-inducing receptor complex (DISC) (Muzio et structurally and functionally related to the nematode al., 1998; Salvesen and Dixit, 1999). Caspase-8 is Ced-4 (Zou et al., 1997). The N-terminal CARD of another mammalian apical caspase linked to death Apaf-1 is required for interaction with the CARD of receptor signaling pathways (Boldin et al., 1996; Muzio caspase-9 and is fused to a centrally located NBD et al., 1996). Caspase-8 binds to its upstream activator (Zou et al., 1997; Li et al., 1997). The NBD of Apaf- FADD (also called MORT1) through an homophilic 1 and Ced-4 is homologous to the ABC-ATP/GTPase interaction via their N-terminal CARD-related a helix- module that is present in a large number of proteins rich domains, namely the death eector domains with diverse biological function (Walker et al., 1982). (DEDs) (Boldin et al., 1995; Chinnaiyan et al., 1995; Both the ABC domain present in these ATP/GTPases Bertin et al., 1997). FADD also has a C-terminal death and the NBD of Apaf-1/Ced-4 contain conserved domain (DD) which binds to DD-containing receptors binding sites for nucleotide (P-loop or Walker's A or adapter molecules and mediates recruitment of box) and Mg2+ (Walker's B box) (Walker et al., caspase-8 to the membrane receptor complex triggered 1982; Seshagiri and Miller, 1997; Chinnaiyan et al., upon binding of the trimeric ligand (Boldin et al., 1995, 1997b; Chaudhary et al., 1998; Jaroszewski et al., 1996; Chinnaiyan et al., 1995; Muzio et al., 1996). 2000). In addition, the NBD of both Apaf-1 and Trimerization of death receptors (DRs) induces the CED-4 mediates protein homooligomerization, a proximity and activation of caspase-8 (Muzio et al., function that is critical for Apaf-1/Ced-4 activity 1998). A model for caspase-8 activation in the tumor (Chaudhary et al., 1998; Yang et al., 1998; Hu et al., necrosis factor receptor-1 (TNFR1) signaling pathway 1998a; Srinivasula et al., 1998). Therefore, we refer is shown in Figure 1b. Although the caspase-8/DISC here to the NBD present in Apaf-1 and homologues and caspase-9/Apaf-1 machineries have signi®cant as nucleotide-binding oligomerization domain (NOD) dierences, enzymatic activation of caspases in both and to structurally related NOD-containing proteins systems appear to require binding to their upstream such as Apaf-1 and Nod1 as Nods. Although the regulators and the induced proximity of apical caspases NOD mediates both nucleotide binding and oligo- though oligomerization (or trimerization) (Inohara et merization, studies with Apaf-1 and Ced-4 have not al., 2000). revealed dierent subdomains within the NOD that mediate these activities (Hu et al., 1998a; Yang et al., 1998). Regulation of Ced-4/Apaf-1 oligomerization and caspase Apaf-1 also has a C-terminal regulatory domain recruitment containing WD40 repeats (WDR), which is essential for the ability of Apaf-1 to respond to cytochrome c Because caspase activation plays a critical role in (Zou et al., 1997; Li et al., 1997; Hu et al., 1999). determining cell fate, oligomerization of caspase Analyses of mice lacking Apaf-1 and caspase-9 activators such as Apaf-1 and the subsequent recruit- revealed that Apaf-1 and caspase-9 play important ment of target caspases to their activators are highly roles in apoptosis during development of multiple regulated events. For example, activation of Ced-3 by tissues including brain, limb and eye, comparable to Ced-4 is regulated by Ced-9.
Load more

Recommended publications
  • The Expression of NOD2, NLRP3 and NLRC5 and Renal Injury in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
    Wang et al. J Transl Med (2019) 17:197 https://doi.org/10.1186/s12967-019-1949-5 Journal of Translational Medicine RESEARCH Open Access The expression of NOD2, NLRP3 and NLRC5 and renal injury in anti-neutrophil cytoplasmic antibody-associated vasculitis Luo‑Yi Wang1,2,3, Xiao‑Jing Sun1,2,3, Min Chen1,2,3* and Ming‑Hui Zhao1,2,3,4 Abstract Background: Nucleotide‑binding oligomerization domain (NOD)‑like receptors (NLRs) are intracellular sensors of pathogens and molecules from damaged cells to regulate the infammatory response in the innate immune system. Emerging evidences suggested a potential role of NLRs in anti‑neutrophil cytoplasmic antibody (ANCA)‑associated vasculitis (AAV). This study aimed to investigate the expression of nucleotide‑binding oligomerization domain con‑ taining protein 2 (NOD2), NOD‑like receptor family pyrin domain containing 3 (NLRP3) and NOD‑like receptor family CARD domain containing 5 (NLRC5) in kidneys of AAV patients, and further explored their associations with clinical and pathological parameters. Methods: Thirty‑four AAV patients in active stage were recruited. Their renal specimens were processed with immu‑ nohistochemistry to assess the expression of three NLRs, and with double immunofuorescence to detect NLRs on intrinsic and infltrating cells. Analysis of gene expression was also adopted in cultured human podocytes. The associa‑ tions between expression of NLRs and clinicopathological parameters were analyzed. Results: The expression of NOD2, NLRP3 and NLRC5 was signifcantly higher in kidneys from AAV patients than those from normal controls, minimal change disease or class IV lupus nephritis. These NLRs co‑localized with podocytes and infltrating infammatory cells.
    [Show full text]
  • Golgi Phosphoprotein 3 Promotes the Proliferation of Gallbladder Carcinoma Cells Via Regulation of the NLRP3 Inflammasome
    ONCOLOGY REPORTS 45: 113, 2021 Golgi phosphoprotein 3 promotes the proliferation of gallbladder carcinoma cells via regulation of the NLRP3 inflammasome ZHENCHENG ZHU1,2*, QINGZHOU ZHU1,2*, DONGPING CAI3, LIANG CHEN4, WEIXUAN XIE2, YANG BAI2 and KUNLUN LUO1,2 1Anhui Medical University, Hefei, Anhui 230032; Departments of 2Hepatobiliary Surgery, 3Laboratory and 4Cardiology, The 904th Hospital of Joint Logistic Support Force of PLA, Wuxi, Jiangsu 214044, P.R. China Received January 18, 2021; Accepted April 2, 2021 DOI: 10.3892/or.2021.8064 Abstract. Golgi phosphoprotein 3 (GOLPH3) has been Introduction demonstrated to promote tumor progression in various gastro‑ intestinal malignancies. However, its effects in gallbladder Gallbladder carcinoma (GBC) is a highly malignant tumor carcinoma (GBC) remain unknown. In the present study, the of the biliary system with a median survival time of only expression levels of GOLPH3 and nucleotide‑binding domain 6 months (1‑3). The primary pathological type of GBC leucine‑rich repeat and pyrin domain containing receptor 3 observed in patients is adenocarcinoma. The effects of current (NLRP3) in human GBC tissues were detected by immuno‑ chemotherapeutic regimens are not sufficient for GBC due histochemistry, and the clinical data and survival of these to the lack of effective drugs, making it particularly difficult patients were analyzed. Next, whether GOLPH3 could affect to control the mortality rate of GBC (3,4). Due to the close tumor proliferation via regulation of the NLRP3 inflamma‑ relationship between inflammation and GBC, investigation of some was investigated in vitro. The results demonstrated that inflammatory‑related molecular mechanisms may highlight GOLPH3 could promote GBC cell proliferation, and that it novel specific targets for the treatment of GBC (4).
    [Show full text]
  • Genetic Variation in Pattern-Recognition Receptors and Association with Leprosy 145
    DOI: 10.5772/intechopen.73871 ProvisionalChapter chapter 8 Genetic Variation inin Pattern-RecognitionPattern-Recognition ReceptorsReceptors and and Association withwith LeprosyLeprosy Karina Talita de Oliveira Santana JorgeJorge andand Frederico Marianetti SorianiSoriani Additional information isis available atat thethe endend ofof thethe chapterchapter http://dx.doi.org/10.5772/intechopen.73871 Abstract Mycobacterium leprae is a highly infectious and low pathogenic microorganism that is the causal agent of leprosy. The differences in vulnerability to leprosy, the spectral immune response, and the clinical manifestations of this disease are related to different genetic backgrounds among individuals. In this sense, genetic variants, especially in genes related to mycobacteria recognition and host immune response, may be key factors to explain individual susceptibility and resistance to leprosy and their conditions. In this chapter, studies regarding association of genetic variants in pattern-recognition receptors (PRRs) and leprosy will be reviewed revealing the importance of molecules such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in leprosy initiation and maintenance. Keywords: polymorphisms, pattern-recognition receptors, mycobacterium leprae, leprosy 1. Introduction Leprosy is caused by Mycobacterium leprae, which is an intracellular bacterium with high infectivity and low pathogenicity. It means that there are a large number of people exposed to this pathogen; however, the majority of them are naturally resistant. On the other hand, some people develop leprosy once challenged with M. leprae. The people who develop disease may present different clinical forms of leprosy. Some of them develop a localized disease, named tuberculoid leprosy, with a strong host response, which does not avoid development of nerve injury and physical disabilities.
    [Show full text]
  • Cytotoxic T Cells Class I- Dependent Lymphocyte Killing by NLRC5 Deficiency Selectively Impairs
    The Journal of Immunology NLRC5 Deficiency Selectively Impairs MHC Class I- Dependent Lymphocyte Killing by Cytotoxic T Cells Francesco Staehli,* Kristina Ludigs,* Leonhard X. Heinz,† Queralt Seguı´n-Este´vez,‡ Isabel Ferrero,x Marion Braun,x Kate Schroder,{ Manuele Rebsamen,† Aubry Tardivel,* Chantal Mattmann,* H. Robson MacDonald,x Pedro Romero,x Walter Reith,‡ Greta Guarda,*,1 and Ju¨rg Tschopp*,1,2 Nucleotide-binding oligomerization domain-like receptors (NLRs) are intracellular proteins involved in innate-driven inflamma- tory responses. The function of the family member NLR caspase recruitment domain containing protein 5 (NLRC5) remains a matter of debate, particularly with respect to NF-kB activation, type I IFN, and MHC I expression. To address the role of NLRC5, we generated Nlrc5-deficient mice (Nlrc5D/D). In this article we show that these animals exhibit slightly decreased CD8+ T cell percentages, a phenotype compatible with deregulated MHC I expression. Of interest, NLRC5 ablation only mildly affected MHC I expression on APCs and, accordingly, Nlrc5D/D macrophages efficiently primed CD8+ T cells. In contrast, NLRC5 deficiency dramatically impaired basal expression of MHC I in T, NKT, and NK lymphocytes. NLRC5 was sufficient to induce MHC I expression in a human lymphoid cell line, requiring both caspase recruitment and LRR domains. Moreover, endogenous NLRC5 localized to the nucleus and occupied the proximal promoter region of H-2 genes. Consistent with downregulated MHC I expression, the elimination of Nlrc5D/D lymphocytes by cytotoxic T cells was markedly reduced and, in addition, we observed low NLRC5 expression in several murine and human lymphoid-derived tumor cell lines.
    [Show full text]
  • Post-Transcriptional Inhibition of Luciferase Reporter Assays
    THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 287, NO. 34, pp. 28705–28716, August 17, 2012 © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A. Post-transcriptional Inhibition of Luciferase Reporter Assays by the Nod-like Receptor Proteins NLRX1 and NLRC3* Received for publication, December 12, 2011, and in revised form, June 18, 2012 Published, JBC Papers in Press, June 20, 2012, DOI 10.1074/jbc.M111.333146 Arthur Ling‡1,2, Fraser Soares‡1,2, David O. Croitoru‡1,3, Ivan Tattoli‡§, Leticia A. M. Carneiro‡4, Michele Boniotto¶, Szilvia Benko‡5, Dana J. Philpott§, and Stephen E. Girardin‡6 From the Departments of ‡Laboratory Medicine and Pathobiology and §Immunology, University of Toronto, Toronto M6G 2T6, Canada, and the ¶Modulation of Innate Immune Response, INSERM U1012, Paris South University School of Medicine, 63, rue Gabriel Peri, 94276 Le Kremlin-Bicêtre, France Background: A number of Nod-like receptors (NLRs) have been shown to inhibit signal transduction pathways using luciferase reporter assays (LRAs). Results: Overexpression of NLRX1 and NLRC3 results in nonspecific post-transcriptional inhibition of LRAs. Conclusion: LRAs are not a reliable technique to assess the inhibitory function of NLRs. Downloaded from Significance: The inhibitory role of NLRs on specific signal transduction pathways needs to be reevaluated. Luciferase reporter assays (LRAs) are widely used to assess the Nod-like receptors (NLRs)7 represent an important class of activity of specific signal transduction pathways. Although pow- intracellular pattern recognition molecules (PRMs), which are erful, rapid and convenient, this technique can also generate implicated in the detection and response to microbe- and dan- www.jbc.org artifactual results, as revealed for instance in the case of high ger-associated molecular patterns (MAMPs and DAMPs), throughput screens of inhibitory molecules.
    [Show full text]
  • Supplementary Table 2 Supplementary Table 1
    Supplementary table 1 Rai/ Binet IGHV Cytogenetic Relative viability Fludarabine- Sex Outcome CD38 (%) IGHV gene ZAP70 (%) Treatment (s) Stage identity (%) abnormalities* increase refractory 1 M 0/A Progressive 14,90 IGHV3-64*05 99,65 28,20 Del17p 18.0% 62,58322819 FCR n.a. 2 F 0/A Progressive 78,77 IGHV3-48*03 100,00 51,90 Del17p 24.8% 77,88052021 FCR n.a. 3 M 0/A Progressive 29,81 IGHV4-b*01 100,00 9,10 Del17p 12.0% 36,48 Len, Chl n.a. 4 M 1/A Stable 97,04 IGHV3-21*01 97,22 18,11 Normal 85,4191657 n.a. n.a. Chl+O, PCR, 5 F 0/A Progressive 87,00 IGHV4-39*07 100,00 43,20 Del13q 68.3% 35,23314039 n.a. HDMP+R 6 M 0/A Progressive 1,81 IGHV3-43*01 100,00 20,90 Del13q 77.7% 57,52490626 Chl n.a. Chl, FR, R-CHOP, 7 M 0/A Progressive 97,80 IGHV1-3*01 100,00 9,80 Del17p 88.5% 48,57389901 n.a. HDMP+R 8 F 2/B Progressive 69,07 IGHV5-a*03 100,00 16,50 Del17p 77.2% 107,9656878 FCR, BA No R-CHOP, FCR, 9 M 1/A Progressive 2,13 IGHV3-23*01 97,22 29,80 Del11q 16.3% 134,5866919 Yes Flavopiridol, BA 10 M 2/A Progressive 0,36 IGHV3-30*02 92,01 0,38 Del13q 81.9% 78,91844953 Unknown n.a. 11 M 2/B Progressive 15,17 IGHV3-20*01 100,00 13,20 Del11q 95.3% 75,52880995 FCR, R-CHOP, BR No 12 M 0/A Stable 0,14 IGHV3-30*02 90,62 7,40 Del13q 13.0% 13,0939004 n.a.
    [Show full text]
  • ATP-Binding and Hydrolysis in Inflammasome Activation
    molecules Review ATP-Binding and Hydrolysis in Inflammasome Activation Christina F. Sandall, Bjoern K. Ziehr and Justin A. MacDonald * Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB T2N 4Z6, Canada; [email protected] (C.F.S.); [email protected] (B.K.Z.) * Correspondence: [email protected]; Tel.: +1-403-210-8433 Academic Editor: Massimo Bertinaria Received: 15 September 2020; Accepted: 3 October 2020; Published: 7 October 2020 Abstract: The prototypical model for NOD-like receptor (NLR) inflammasome assembly includes nucleotide-dependent activation of the NLR downstream of pathogen- or danger-associated molecular pattern (PAMP or DAMP) recognition, followed by nucleation of hetero-oligomeric platforms that lie upstream of inflammatory responses associated with innate immunity. As members of the STAND ATPases, the NLRs are generally thought to share a similar model of ATP-dependent activation and effect. However, recent observations have challenged this paradigm to reveal novel and complex biochemical processes to discern NLRs from other STAND proteins. In this review, we highlight past findings that identify the regulatory importance of conserved ATP-binding and hydrolysis motifs within the nucleotide-binding NACHT domain of NLRs and explore recent breakthroughs that generate connections between NLR protein structure and function. Indeed, newly deposited NLR structures for NLRC4 and NLRP3 have provided unique perspectives on the ATP-dependency of inflammasome activation. Novel molecular dynamic simulations of NLRP3 examined the active site of ADP- and ATP-bound models. The findings support distinctions in nucleotide-binding domain topology with occupancy of ATP or ADP that are in turn disseminated on to the global protein structure.
    [Show full text]
  • Inflammasome Activation and Regulation
    Zheng et al. Cell Discovery (2020) 6:36 Cell Discovery https://doi.org/10.1038/s41421-020-0167-x www.nature.com/celldisc REVIEW ARTICLE Open Access Inflammasome activation and regulation: toward a better understanding of complex mechanisms Danping Zheng1,2,TimurLiwinski1,3 and Eran Elinav 1,4 Abstract Inflammasomes are cytoplasmic multiprotein complexes comprising a sensor protein, inflammatory caspases, and in some but not all cases an adapter protein connecting the two. They can be activated by a repertoire of endogenous and exogenous stimuli, leading to enzymatic activation of canonical caspase-1, noncanonical caspase-11 (or the equivalent caspase-4 and caspase-5 in humans) or caspase-8, resulting in secretion of IL-1β and IL-18, as well as apoptotic and pyroptotic cell death. Appropriate inflammasome activation is vital for the host to cope with foreign pathogens or tissue damage, while aberrant inflammasome activation can cause uncontrolled tissue responses that may contribute to various diseases, including autoinflammatory disorders, cardiometabolic diseases, cancer and neurodegenerative diseases. Therefore, it is imperative to maintain a fine balance between inflammasome activation and inhibition, which requires a fine-tuned regulation of inflammasome assembly and effector function. Recently, a growing body of studies have been focusing on delineating the structural and molecular mechanisms underlying the regulation of inflammasome signaling. In the present review, we summarize the most recent advances and remaining challenges in understanding the ordered inflammasome assembly and activation upon sensing of diverse stimuli, as well as the tight regulations of these processes. Furthermore, we review recent progress and challenges in translating inflammasome research into therapeutic tools, aimed at modifying inflammasome-regulated human diseases.
    [Show full text]
  • Functional Screening of ¢Ve PYPAF Family Members Identi¢Es PYPAF5 As a Novel Regulator of NF-UB and Caspase-1
    FEBS 26602 FEBS Letters 530 (2002) 73^78 Functional screening of ¢ve PYPAF family members identi¢es PYPAF5 as a novel regulator of NF-UB and caspase-1 Jill M.Grenier 1, Lin Wang1, Gulam A.Manji 2, Waan-Jeng Huang, Amal Al-Garawi, Roxanne Kelly, Adam Carlson, Sarah Merriam, Jose M.Lora, Michael Briskin, Peter S.DiStefano 3, John Bertinà Millennium Pharmaceuticals Inc., 75 Sidney Street, Cambridge, MA 02139, USA Received 22 August 2002; accepted 28 August 2002 First published online 26 September 2002 Edited by Veli-Pekka Lehto activates pro-caspase-9.Apaf-1 has a tripartite domain struc- Abstract PYRIN-containing Apaf-1-like proteins (PYPAFs) are a recently identi¢ed family of proteins thought to function ture consisting of an N-terminal caspase-recruitment domain in apoptotic and in£ammatory signaling pathways. PYPAF1 (CARD) that mediates recruitment of pro-caspase-9 to the and PYPAF7 proteins have been found to assemble with the apoptosome, a central nucleotide-binding site (NBS) domain, PYRIN^CARD protein ASC and coordinate the activation of and a C-terminal domain comprised of WD-40 repeats.The NF-UB and pro-caspase-1. To determine if other PYPAF family NBS domain mediates Apaf-1 oligomerization in the presence members function in pro-in£ammatory signaling pathways, we of dATP, whereas the WD-40 repeats function as binding sites screened ¢ve other PYPAF proteins (PYPAF2, PYPAF3, PY- for cytochrome c.Thus, Apaf-1 functions as a sensor-like PAF4, PYPAF5 and PYPAF6) for their ability to activate NF- molecule that signals apoptosis in response to the release of U B and pro-caspase-1.
    [Show full text]
  • NLR Members in Inflammation-Associated
    Cellular & Molecular Immunology (2017) 14, 403–405 & 2017 CSI and USTC All rights reserved 2042-0226/17 $32.00 www.nature.com/cmi RESEARCH HIGHTLIGHT NLR members in inflammation-associated carcinogenesis Ha Zhu1,2 and Xuetao Cao1,2,3 Cellular & Molecular Immunology (2017) 14, 403–405; doi:10.1038/cmi.2017.14; published online 3 April 2017 hronic inflammation is regarded as an impor- nucleotide-binding and oligomerization domain IL-2,8 and NAIP was found to regulate the STAT3 Ctant factor in cancer progression. In addition (NOD)-like receptors (NLRs). TLRs and CLRs are pathway independent of inflammasome formation.9 to the immune surveillance function in the early located in the plasma membranes, whereas RLRs, The AOM/DSS model is the most popular model stage of tumorigenesis, inflammation is also known ALRs and NLRs are intracellular PRRs.3 Unlike used to study the function of NLRs in fl fl as one of the hallmarks of cancer and can supply other families that have been shown to bind their in ammation-associated carcinogenesis. In amma- the tumor microenvironment with bioactive mole- specific cognate ligands, the distinct ligands for somes initiated by NLRs or AIM2 have been widely cules and favor the development of other hallmarks NLRs are still unknown. In fact, mounting evidence reported to participate in the maintenance of 10,11 Nlrp3 Nlrp6 of cancer, such as genetic instability and angiogen- suggests that NLRs function as cytoplasmic sensors intestinal homeostasis. -/-, -/-, Nlrc4 Nlrp1 Nlrx1 Nlrp12 esis. Moreover, inflammation contributes to the and participate in modulating TLR, RLR and CLR -/-, -/-, -/- and -/- mice are 4 more susceptible to AOM/DSS-induced colorectal changing tumor microenvironment by altering signaling pathways.
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Apoptosis Ligand-Induced Enhanced Resistance to Fas/Fas
    Theileria parva-Transformed T Cells Show Enhanced Resistance to Fas/Fas Ligand-Induced Apoptosis This information is current as Peter Küenzi, Pascal Schneider and Dirk A. E. Dobbelaere of October 2, 2021. J Immunol 2003; 171:1224-1231; ; doi: 10.4049/jimmunol.171.3.1224 http://www.jimmunol.org/content/171/3/1224 Downloaded from References This article cites 69 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/171/3/1224.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 2, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Theileria parva-Transformed T Cells Show Enhanced Resistance to Fas/Fas Ligand-Induced Apoptosis1 Peter Ku¨enzi,2* Pascal Schneider,† and Dirk A. E. Dobbelaere3* Lymphocyte homeostasis is regulated by mechanisms that control lymphocyte proliferation and apoptosis. Activation-induced cell death is mediated by the expression of death ligands and receptors, which, when triggered, activate an apoptotic cascade.
    [Show full text]