MCC950 closes the active conformation of NLRP3 to an inactive state

Tapia-Abellán, Ana; Angosto-Bazarra, Diego; Martínez-Banaclocha, Helios; Torre‐Minguela, Carlos de; Cerón‐Carrasco, José P.; Pérez‐Sánchez, Horacio; Aróstegui, Juan I.; Pelegrı́n, Pablo

doi:10.1038/s41589-019-0278-6

Cited by 329 publications

(308 citation statements)

References 32 publications

(32 reference statements)

Supporting

Mentioning

287

Contrasting

Unclassified

Order By: Relevance

“…S1A,B). Also, as previously described [19,27], the pathological mutation of NLRP3 D303N associated with cryopyrin associated periodic syndromes (CAPS) resulted in spontaneous oligomerization of NLRP3 when expressed in HEK293 cells without any stimulation (Fig. 1C).…”

Section: Nlrp3 But Not Asc Oligomerize In Response To K + Effluxsupporting

confidence: 79%

ASC oligomer favor caspase-1^CARDdomain recruitment after intracellular potassium efflux

Martín-Sánchez

Compan

Tapia-Abellán

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Signaling through the inflammasome is important for the inflammatory response. Low concentrations of intracellular K + are associated with the specific oligomerization and activation of the NLRP3 inflammasome, a type of inflammasome involved in sterile inflammation. Subsequent to NLRP3 oligomerization, ASC protein binds and form oligomeric filaments culminating in large protein complexes named ASC specks. ASC specks are also initiated from different inflammasome scaffolds, as AIM2, NLRC4 or Pyrin. ASC oligomers induce the recruitment of caspase-1 through interactions between their respective caspase activation and recruitment domains (CARD), and favoring its activation. So far ASC oligomerization and caspase-1 activation are considered as a K +independent process. Here we found that ASC oligomers change their structure upon low intracellular K + independently of NLRP3 and allow the ASC CARD domain to be more accessible for the recruitment of pro-caspase-1 CARD domain. Therefore, conditions that decrease intracellular K + not only drive NLRP3 responses, but also enhance the recruitment of pro-caspase-1 by ASC specks formed by different inflammasomes, indicating that intracellular K + homeostasis is a key regulatory step for inflammasome regulation.the SPF-animal house from IMIB-Arrixaca for mice colony maintenance. We thank the members of the Pelegrin's laboratory for comments and suggestions.

show abstract

Section: Nlrp3 But Not Asc Oligomerize In Response To K + Effluxsupporting

confidence: 79%

ASC oligomer favor caspase-1^CARDdomain recruitment after intracellular potassium efflux

Martín-Sánchez

Compan

Tapia-Abellán

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…1C). In contrast, the NLRP3-specific inhibitor, MCC950 ( 14) , failed to prevent BTK-specific interaction and NLRP3 p-Y positivity (Fig. 1J).…”

Section: Resultsmentioning

confidence: 93%

BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity

Bittner

Liu

Dickhöfer

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Activity of the NLRP3 inflammasome, a critical mediator of inflammation (1), is controlled by accessory proteins (2, 3), post-translational modifications (4, 5), cellular localization (6, 7) and oligomerization (8). How these factors relate, is unclear. We show that the established drug target, Bruton’s Tyrosine Kinase (BTK) (2, 9), integrates several levels of NLRP3 regulation: BTK phosphorylation of four conserved tyrosine residues, by neutralizing the charge of a polybasic linker region, weakens the interaction of NLRP3 with Golgi phospholipids and may thus guide NLRP3 cytosolic localization. BTK activity also promotes NLRP3 oligomerization and subsequent formation of inflammasomes. As NLRP3 tyrosine modification ultimately also impacts on IL-1β release, we propose BTK-mediated, charge-switch-based NLRP3 regulation as a novel and therapeutically tractable step in the control of inflammation.One Sentence SummaryMulti-phosphorylation of NLRP3 by Bruton’s tyrosine kinase modulates NLRP3 cellular localization, inflammasome assembly, and IL-1β release.

show abstract

“…The compound MCC950 (also known as CRID3) is the NLRP3 inhibitor that has been the most studied to date . MCC950 inhibits NLRP3 by directly interacting with the NLRP3 ATPase domain, thereby blocking ATP hydrolysis and NLRP3 oligomerization . Several studies have shown therapeutic efficacy of MCC950 in a variety of preclinical mouse models, including atherosclerosis, experimental autoimmune encephalomyelitis, diabetes, steatohepatitis, and colitis .…”

Section: Inflammasome‐targeted Therapies In Arthritic Diseasesmentioning

confidence: 99%

“…151,152 MCC950 inhibits NLRP3 by directly interacting with the NLRP3 ATPase domain, thereby blocking ATP hydrolysis and NLRP3 oligomerization. 151,153 Several studies have shown therapeutic efficacy of MCC950 in a variety of preclinical mouse models, including atherosclerosis, experimental autoimmune encephalomyelitis, diabetes, steatohepatitis, and colitis. 17 First, before its identification as a NLRP3 targeting molecule, MCC950 was discovered as an inhibitor of IL-1β activation.…”

Section: Nlrp3 Inhibitorsmentioning

confidence: 99%

Inflammasomes contributing to inflammation in arthritis

Spel

Martinon

2020

Immunological Reviews

117

View full text Add to dashboard Cite

Inflammasomes are intracellular multiprotein signaling platforms that initiate inflammatory responses in response to pathogens and cellular damage. Active inflammasomes induce the enzymatic activity of caspase‐1, resulting in the induction of inflammatory cell death, pyroptosis, and the maturation and secretion of inflammatory cytokines IL‐1β and IL‐18. Inflammasomes are activated in many inflammatory diseases, including autoinflammatory disorders and arthritis, and inflammasome‐specific therapies are under development for the treatment of inflammatory conditions. In this review, we outline the different inflammasome platforms and recent findings contributing to our knowledge about inflammasome biology in health and disease. In particular, we discuss the role of the inflammasome in the pathogenesis of arthritic diseases, including rheumatoid arthritis, gout, ankylosing spondylitis, and juvenile idiopathic arthritis, and the potential of newly developed therapies that specifically target the inflammasome or its products for the treatment of inflammatory diseases.

show abstract

MCC950 closes the active conformation of NLRP3 to an inactive state

Cited by 329 publications

References 32 publications

ASC oligomer favor caspase-1^CARDdomain recruitment after intracellular potassium efflux

ASC oligomer favor caspase-1^CARDdomain recruitment after intracellular potassium efflux

BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity

Inflammasomes contributing to inflammation in arthritis

Contact Info

Product

Resources

About

MCC950 closes the active conformation of NLRP3 to an inactive state

Cited by 329 publications

References 32 publications

ASC oligomer favor caspase-1CARDdomain recruitment after intracellular potassium efflux

ASC oligomer favor caspase-1CARDdomain recruitment after intracellular potassium efflux

BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity

Inflammasomes contributing to inflammation in arthritis

Contact Info

Product

Resources

About

ASC oligomer favor caspase-1^CARDdomain recruitment after intracellular potassium efflux

ASC oligomer favor caspase-1^CARDdomain recruitment after intracellular potassium efflux