Cytosolic proteins NODs involved in the regulation of immune and inflammatory responses. HU Chao - feng

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1 1304 Chinese Journal of Pathophysiology 2004,20 (7) : [ ] (2004) NODs (, ) Cytosolic proteins NODs involved in the regulation of immune and inflammatory responses HU Chao - feng ( Department of Pathophysiology, Medical College of Jinan University, Guangzhou , China) A Review Nucleotide - binding oligomerization domain (NOD) proteins are members of a growing family of cytosolic factors related to the apoptosis regulator Apaf - 1 and a class of plant disease resistance pro2 teins. NOD proteins have been implicated in the induction of NF -B activity and in the activation of caspas2 es. Biochemical evidence has unraveled the role of NOD1 and NOD2 as intracellular sensors of bacterial pepti2 doglycan. Notably, genetic variation in the genes encoding the NOD proteins NOD2, cryopyrin and C TA in humans is associated with inflammatory disease or increased susceptibility to bacterial infections. NOD proteins may be involved in the recognition of microorganisms and regulation of inflammatory responses. [] NOD ; ; ; [ KEY WORDS] NOD proteins ; Inflammation ; Immunity ; Apoptosis [] R363 [] A [2 ], 1 NOD, (pattern - recognition receptors,prrs) (pathogen - associated molecular [ ] [ ] Tel : NOD,PRRs - 1 (apoptotic protease activating factor - 1, APAF - 1) [3, 4 ] ;,NOD1 NOD2, NOD patterns, PAMPs), Toll ( Toll - like, 20 APAF - 1 receptors,tlrs) PRRs NOD1 NOD TLRs NF - B 3 - N -, (effector - binding domain, EBD), [1 ],PRRs, NOD, C - ( ligand - TLRs,PAMPs, recognition domain, LRD) ( 1) NOD NOD EBD,cas2, pase (caspase - recruitment domain, CARD) pyrin (pyrin domain, PYD) - (nucleotide - binding oligomeriza2 [5,6 ] CARD PYD tion domain, NOD), NOD1 1 CARD,NOD2 2 CARDs PYD NOD DEFCAP(death effector fil2 ament - forming Ced like apoptosis protein) cryopy2

2 1305 rin PYPAFs (pyrin - containing APAF like pro2 teins) 15 NOD CARDs NF - B,, (neuronal apopto2 sis inhibitory protein, NAIP),NAIP NOD [9-11 ] IL - 1,N - 3 (interleukin - 1 beta converting en2 (baculovirus inhibitor - of - apoptosis repeats, BIRs) [7 ] (major histocompati2 bility complex, MHC) (class trans2 activator, C TA ) N - EBD NOD ( C TA CARD ),N - C TA DNA,,Caspase - 1 caspase - 9 MHC [8] NOD8 LRD CARD NOD1 caspase - 9 CARD PYD NOD,DEFCAP C - CARD APAF - 1 C - pase - 1 CARD - CARD cas2 WD - 40 (WD - 40 repeats, WDRs) [7] Fig 1 Domain structures of NOD proteins [7 ]. 1 NOD 2 NOD 211 NF - B NOD1, TLRs NOD NOD2 NF - B,; A2 PAF - 1 NF - B, NOD1 NOD2 A2 PAF - 1 LPS,(peptidoglycan, NOD C - PGN),LPS (leucine - rich repeats, LRRs),LRRs NF - B, LRRs NOD1 NOD2 NF -B, LRRs NOD NF - B,LRRs NOD,NOD1 NOD2 LRRs,NF - B : LRRs NF - B 1 2 CARDs NF - B, NOD1 NOD2 CARD NF - B NOD zyme - protease - activating factor, IPAF) cryopyrin PY2 PAF5 PYPAF7 NF -B 212 NOD, APAF - NOD1 NOD2 IPAF DEFCAP caspases, Caspase,, ;,NOD1 cas2 pase - 1, IPAF cryopyrin DEFCAP PY2 PAF5 PYPAF7 caspase - 1 [7, 12, 13 ] APAF - 1 WD - 40 c,nod APAF - 1,APAF - 1 CARD cas2 pase - 9 CARD, caspase - 9 [14 ] NOD caspases NOD,NOD,NOD caspases 3 NOD1 NOD2 NOD (disease - resistance proteins, R proteins),r,, R,NOD1 NOD2 LPS ;,NOD1 NOD2 [15 ] N - (N - acetylglucosamine, GlcNAc or G) N - (N - acetylmuramic acid, MurNac or M) (Lys),

3 1306 (diaminopimelic acid, DAP) Girardin [16 ] TLRs,,TLRs NOD HEK293T NOD1 ;NOD1 DAP GM ( Glc2 NAc - MurNac - tripeptide, GM - tripeptide),gm - L - Ala - D - Glu - mesodapchamaillard [17 ] Lys DAP NOD1 ; - (D - glutamine - diaminopimelic acid, D - Glu - DAP) NOD1 ing protein (RIP) - like interacting caspase - like apopto2,d - Glu - DAP sis - regulatory protein (CLARP ) kinase ], Girardin [16 ],NOD1 CARD - CARD, NF -B ( 2) ; GM - tripeptide NOD2 GM - tripeptide, ), RICK (muramyl dipeptide, MDP) MurNac - L - Ala - D - isogln NOD2 [29 ],D - Ala L - Ala L - isogln D - isogln, MDP NOD2 D - Glu - DAP MDP, TNF; NOD - / - MDP, D - Glu - DAP MDP, IKK,IKKIB,,IL - 1 TNF ; IL - 6 IL - 12, T T ; NOD2 4 NOD Inohara [7 ],NOD1 NOD2 LRRs, EBDs,CARDs NOD1 NOD2 - RICK[ receptor - interact2 MyD88 ( TLRs NOD1 NOD2 NF - B,RICK,NF -B [18 ] IKK / IKK / IKK( IB, IKK ),NF - B IB,RICK CARD IKK,NF -B,,, [19 ] IKK Fig 2 Signalling pathways mediated by NOD1, NOD2, IPAF and cryopyrin. 2 NOD1, NOD2, IPAF cryopyrin

4 1307 NOD ASC (apoptosis - associated speck - like protein containing a caspase recruitment do2 main),asc N - PYD, C - [26 ] CARDASC PYD NOD, cryopyrinpypaf5 PYPAF7 CARD IPAF NF - B [12, 13, 20, 21 ], ASC PYD (familial cold autoinflamma2 cryopyrin PYD,ASC CARD IPAF CARD,ASC syndrome, MWs) ; ASC RICK ( neonatal - onset multisystem inflammatory disease,,ikk NF -B, NOD [27, 28 ],cryopyrin pyrin,n - PYD,pyrin PYD ASC PYD MID, cryopyrin IPAF NF - B [20, 21 ],pyrin cryopyrin IPAF, ( 2) NOD,, NOD NOD1 NOD2,NOD 5 NOD C TA NOD2 cryopyrin 3 NOD C TA ( type bare lymphocyte syndrome, BLS),BLS, Nature Rev Immunol, 2001, 1 (2) : MHC [8 ], MHC [2 ] Inohara N, Ogura Y, Nugez G. NODs : a family of cytosolic proteins that regulate the host response to pathogens[j ]. Curr T, Opin Microbiol, 2002, 5 (1) : BLS, [3 ] Kanuka H, Sawamoto K, Inohara N, et al. HAC - 1, a Drosophila homolog of APAF - 1 and CED - 4 functions in de2 NOD2 Crohn s velopmental and radiation - induced apoptosis[j ]. Mol Cell, (Crohn s disease, CD),Hugot CD 1999, 4 (5) : NOD2,3 [4 ] Inohara N, Nunez G. The NOD : a signaling molecule that CD, : regulates apoptosis and host defense against pathogens [ J ]. (Arg702Trp Gly908Arg) (3020insC) [22-24 ] PGN MDP, 3 CD NOD2 NF - B new apoptotic signaling motif[j ]. Trends Biochem Sci, 1997, 22 (5) : ,, [6 ] Bertin K, DiStefano PS. The PYRIN domain : a novel motif found in apoptosis and inflammation proteins[j ]. Cell Death CD, Differ, 2000,7 (12) : CD, NOD2 Blau [7 ] Inohara N, Nugez G. NODS: intracellular proteins involved in (Blau syndrome, BS),BS inflammation and apoptosis[j ]. Nature Rev Immunol, 2003, CD BS 3 (5) : , [8 ] Steimle V, Otten LA, Zufferey M, et al. Complementation CD NOD2 LRRs LRRs,BS NOD2 NOD [25 ],BS NOD2 NF - B cryopyrin CIAS1, tory syndrome, FCAS), MW (Muckle - Wells NOMID) FCAS MWs NOMID cryopyrin NF -B, FCAS MWs NO2 NOD NOD TLRs NOD NOD [ ] [1 ] Medzhitov R. Toll - like receptors and innate immunity[j ]. Oncogene, 2001, 20 (44) : [5 ] Hofmann K, Bucher P, Tschopp J. The CARD domain : a cloning of an MHC class II transactivator mutated in hereditary

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