7wge

Human NLRP1 complexed with thioredoxinHuman NLRP1 complexed with thioredoxin

Structural highlights

7wge is a 2 chain structure with sequence from Homo sapiens and Spodoptera frugiperda. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.4Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NLRP1_HUMAN Vitiligo-associated autoimmune disease;Vitiligo;Corneal intraepithelial dyskeratosis with palmoplantar hyperkeratosis and laryngeal dyskeratosis. Disease susceptibility is associated with variations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease may be caused by mutations affecting the gene represented in this entry.

Function

NLRP1_HUMAN As the sensor component of the NLRP1 inflammasome, plays a crucial role in innate immunity and inflammation. In response to pathogens and other damage-associated signals, initiates the formation of the inflammasome polymeric complex, made of NLRP1, CASP1, and possibly PYCARD. Recruitment of proCASP1 to the inflammasome promotes its activation and CASP1-catalyzed IL1B and IL18 maturation and secretion in the extracellular milieu. Activation of NLRP1 inflammasome is also required for HMGB1 secretion. The active cytokines and HMGB1 stimulate inflammatory responses. Inflammasomes can also induce pyroptosis, an inflammatory form of programmed cell death (PubMed:22665479, PubMed:17418785). May be activated by muramyl dipeptide (MDP), a fragment of bacterial peptidoglycan, in a NOD2-dependent manner (PubMed:18511561). Contrary to its mouse ortholog, not activated by Bacillus anthracis lethal toxin (PubMed:19651869). It is unclear whether isoform 2 is involved in inflammasome formation. It is not cleaved within the FIIND domain, does not assemble into specks, nor promote IL1B release (PubMed:22665479). However, in an vitro cell-free system, it has been shown to be activated by MDP (PubMed:17349957). Binds ATP (PubMed:11113115, PubMed:15212762).[UniProtKB:A1Z198]^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8]

Publication Abstract from PubMed

Inflammasome sensors detect pathogen- and danger-associated molecular patterns and promote inflammation and pyroptosis(1). NLRP1 was the first inflammasome sensor to be described, and its hyperactivation is linked to autoinflammatory disease and cancer(2-6). However, the mechanism underlying the activation and regulation of NLRP1 has not been clearly elucidated(4,7,8). Here we identify ubiquitously expressed endogenous thioredoxin (TRX) as a binder of NLRP1 and a suppressor of the NLRP1 inflammasome. The cryo-electron microscopy structure of human NLRP1 shows NLRP1 bound to Spodoptera frugiperda TRX. Mutagenesis studies of NLRP1 and human TRX show that TRX in the oxidized form binds to the nucleotide-binding domain subdomain of NLRP1. This observation highlights the crucial role of redox-active cysteines of TRX in NLRP1 binding. Cellular assays reveal that TRX suppresses NLRP1 inflammasome activation and thus negatively regulates NLRP1. Our data identify the TRX system as an intrinsic checkpoint for innate immunity and provide opportunities for future therapeutic intervention in NLRP1 inflammasome activation targeting this system.

Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome.,Zhang Z, Shibata T, Fujimura A, Kitaura J, Miyake K, Ohto U, Shimizu T Nature. 2023 Oct;622(7981):188-194. doi: 10.1038/s41586-023-06532-4. Epub 2023 , Sep 13. PMID:37704723^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Chu ZL, Pio F, Xie Z, Welsh K, Krajewska M, Krajewski S, Godzik A, Reed JC. A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis. J Biol Chem. 2001 Mar 23;276(12):9239-45. doi: 10.1074/jbc.M006309200. Epub 2000 , Dec 11. PMID:11113115 doi:http://dx.doi.org/10.1074/jbc.M006309200
↑ Liu F, Lo CF, Ning X, Kajkowski EM, Jin M, Chiriac C, Gonzales C, Naureckiene S, Lock YW, Pong K, Zaleska MM, Jacobsen JS, Silverman S, Ozenberger BA. Expression of NALP1 in cerebellar granule neurons stimulates apoptosis. Cell Signal. 2004 Sep;16(9):1013-21. PMID:15212762 doi:10.1016/j.cellsig.2004.02.006
↑ Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell. 2007 Mar 9;25(5):713-24. PMID:17349957 doi:10.1016/j.molcel.2007.01.032
↑ Bruey JM, Bruey-Sedano N, Luciano F, Zhai D, Balpai R, Xu C, Kress CL, Bailly-Maitre B, Li X, Osterman A, Matsuzawa S, Terskikh AV, Faustin B, Reed JC. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell. 2007 Apr 6;129(1):45-56. doi: 10.1016/j.cell.2007.01.045. PMID:17418785 doi:http://dx.doi.org/10.1016/j.cell.2007.01.045
↑ Hsu LC, Ali SR, McGillivray S, Tseng PH, Mariathasan S, Humke EW, Eckmann L, Powell JJ, Nizet V, Dixit VM, Karin M. A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7803-8. doi:, 10.1073/pnas.0802726105. Epub 2008 May 29. PMID:18511561 doi:http://dx.doi.org/10.1073/pnas.0802726105
↑ Liao KC, Mogridge J. Expression of Nlrp1b inflammasome components in human fibroblasts confers susceptibility to anthrax lethal toxin. Infect Immun. 2009 Oct;77(10):4455-62. doi: 10.1128/IAI.00276-09. Epub 2009 Aug, 3. PMID:19651869 doi:http://dx.doi.org/10.1128/IAI.00276-09
↑ Finger JN, Lich JD, Dare LC, Cook MN, Brown KK, Duraiswami C, Bertin J, Gough PJ. Autolytic proteolysis within the function to find domain (FIIND) is required for NLRP1 inflammasome activity. J Biol Chem. 2012 Jul 20;287(30):25030-7. doi: 10.1074/jbc.M112.378323. Epub 2012, Jun 4. PMID:22665479 doi:http://dx.doi.org/10.1074/jbc.M112.378323
↑ Zhong FL, Mamai O, Sborgi L, Boussofara L, Hopkins R, Robinson K, Szeverenyi I, Takeichi T, Balaji R, Lau A, Tye H, Roy K, Bonnard C, Ahl PJ, Jones LA, Baker PJ, Lacina L, Otsuka A, Fournie PR, Malecaze F, Lane EB, Akiyama M, Kabashima K, Connolly JE, Masters SL, Soler VJ, Omar SS, McGrath JA, Nedelcu R, Gribaa M, Denguezli M, Saad A, Hiller S, Reversade B. Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation. Cell. 2016 Sep 22;167(1):187-202.e17. doi: 10.1016/j.cell.2016.09.001. PMID:27662089 doi:http://dx.doi.org/10.1016/j.cell.2016.09.001
↑ Zhang Z, Shibata T, Fujimura A, Kitaura J, Miyake K, Ohto U, Shimizu T. Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome. Nature. 2023 Oct;622(7981):188-194. PMID:37704723 doi:10.1038/s41586-023-06532-4

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OCA

[1] Chu ZL, Pio F, Xie Z, Welsh K, Krajewska M, Krajewski S, Godzik A, Reed JC. A novel enhancer of the Apaf1 apoptosome involved in cytochrome c-dependent caspase activation and apoptosis. J Biol Chem. 2001 Mar 23;276(12):9239-45. doi: 10.1074/jbc.M006309200. Epub 2000 , Dec 11. PMID:11113115 doi:http://dx.doi.org/10.1074/jbc.M006309200

[2] Liu F, Lo CF, Ning X, Kajkowski EM, Jin M, Chiriac C, Gonzales C, Naureckiene S, Lock YW, Pong K, Zaleska MM, Jacobsen JS, Silverman S, Ozenberger BA. Expression of NALP1 in cerebellar granule neurons stimulates apoptosis. Cell Signal. 2004 Sep;16(9):1013-21. PMID:15212762 doi:10.1016/j.cellsig.2004.02.006

[3] Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E, Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell. 2007 Mar 9;25(5):713-24. PMID:17349957 doi:10.1016/j.molcel.2007.01.032

[4] Bruey JM, Bruey-Sedano N, Luciano F, Zhai D, Balpai R, Xu C, Kress CL, Bailly-Maitre B, Li X, Osterman A, Matsuzawa S, Terskikh AV, Faustin B, Reed JC. Bcl-2 and Bcl-XL regulate proinflammatory caspase-1 activation by interaction with NALP1. Cell. 2007 Apr 6;129(1):45-56. doi: 10.1016/j.cell.2007.01.045. PMID:17418785 doi:http://dx.doi.org/10.1016/j.cell.2007.01.045

[5] Hsu LC, Ali SR, McGillivray S, Tseng PH, Mariathasan S, Humke EW, Eckmann L, Powell JJ, Nizet V, Dixit VM, Karin M. A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in response to Bacillus anthracis infection and muramyl dipeptide. Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7803-8. doi:, 10.1073/pnas.0802726105. Epub 2008 May 29. PMID:18511561 doi:http://dx.doi.org/10.1073/pnas.0802726105

[6] Liao KC, Mogridge J. Expression of Nlrp1b inflammasome components in human fibroblasts confers susceptibility to anthrax lethal toxin. Infect Immun. 2009 Oct;77(10):4455-62. doi: 10.1128/IAI.00276-09. Epub 2009 Aug, 3. PMID:19651869 doi:http://dx.doi.org/10.1128/IAI.00276-09

[7] Finger JN, Lich JD, Dare LC, Cook MN, Brown KK, Duraiswami C, Bertin J, Gough PJ. Autolytic proteolysis within the function to find domain (FIIND) is required for NLRP1 inflammasome activity. J Biol Chem. 2012 Jul 20;287(30):25030-7. doi: 10.1074/jbc.M112.378323. Epub 2012, Jun 4. PMID:22665479 doi:http://dx.doi.org/10.1074/jbc.M112.378323

[8] Zhong FL, Mamai O, Sborgi L, Boussofara L, Hopkins R, Robinson K, Szeverenyi I, Takeichi T, Balaji R, Lau A, Tye H, Roy K, Bonnard C, Ahl PJ, Jones LA, Baker PJ, Lacina L, Otsuka A, Fournie PR, Malecaze F, Lane EB, Akiyama M, Kabashima K, Connolly JE, Masters SL, Soler VJ, Omar SS, McGrath JA, Nedelcu R, Gribaa M, Denguezli M, Saad A, Hiller S, Reversade B. Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation. Cell. 2016 Sep 22;167(1):187-202.e17. doi: 10.1016/j.cell.2016.09.001. PMID:27662089 doi:http://dx.doi.org/10.1016/j.cell.2016.09.001

[9] Zhang Z, Shibata T, Fujimura A, Kitaura J, Miyake K, Ohto U, Shimizu T. Structural basis for thioredoxin-mediated suppression of NLRP1 inflammasome. Nature. 2023 Oct;622(7981):188-194. PMID:37704723 doi:10.1038/s41586-023-06532-4

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