NLRP1: a jack of all trades, or a master of one?

Bachovchin, Daniel A.

doi:10.1016/j.molcel.2021.01.001

Cited by 24 publications

(33 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Each inflammasome is a multi-protein complex that mediates the activation of caspase-1, which promotes the secretion of the pro-inflammatory cytokines IL-1β and IL-18 [ 42 ]. DPP9 inhibition can activate the NLRP1b inflammasome, which in turn activates caspase-1 [ 17 , 18 , 20 , 43 , 44 ]. We wondered if ARI-4175 could affect the inflammasome pathway in HCC and then measured the intrahepatic levels of pro-caspase-1 (full length) and activated caspase-1 (cleaved form, called p20) by Western blotting.…”

Section: Resultsmentioning

confidence: 99%

“…18 [42]. DPP9 inhibition can activate the NLRP1b inflammasome, which in turn activates caspase-1 [17,18,20,43,44]. We wondered if ARI-4175 could affect the inflammasome pathway in HCC and then measured the intrahepatic levels of pro-caspase-1 (full length) and activated caspase-1 (cleaved form, called p20) by Western blotting.…”

Section: Ari-4175 Activation Of a Caspase-1 Mediated Inflammasone Pathwaymentioning

confidence: 99%

See 1 more Smart Citation

Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma

Henderson

Xiang

Huang

et al. 2021

Cancers

View full text Add to dashboard Cite

The mRNA expression of the dipeptidyl peptidase 4 (DPP4) gene family is highly upregulated in human hepatocellular carcinoma (HCC) and is associated with poor survival in HCC patients. Compounds that inhibit the DPP4 enzyme family, such as talabostat and ARI-4175, can mediate tumour regression by immune-mediated mechanisms that are believed to include NLRP1 activation. This study investigated the expression and activity of the DPP4 family during the development of HCC and evaluated the efficacy of ARI-4175 in the treatment of early HCC in mice. This first report on this enzyme family in HCC-bearing mice showed DPP9 upregulation in HCC, whereas intrahepatic DPP8/9 and DPP4 enzyme activity levels decreased with age. We demonstrated that ARI-4175 significantly lowered the total number of macroscopic liver nodules in these mice. In addition, ARI-4175 increased intrahepatic inflammatory cell infiltration, including CD8+ T cell numbers, into the HCC-bearing livers. Furthermore, ARI-4175 activated a critical component of the inflammasome pathway, caspase-1, in these HCC-bearing livers. This is the first evidence of caspase-1 activation by a pan-DPP inhibitor in the liver. Our data suggest that targeting the DPP4 enzyme family may be a novel and effective approach to promote anti-tumour immunity in HCC via caspase-1 activation.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Ari-4175 Activation Of a Caspase-1 Mediated Inflammasone Pathwaymentioning

confidence: 99%

Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma

Henderson

Xiang

Huang

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…Of these three triggers, only DPP8/9 inhibitors also activate the rat and mouse NLRP1 inflammasomes ( 15 ) and the human CARD8 inflammasome (rodents do not express CARD8) ( 13, 18 ). As such, only DPP8/9 inhibitors, and not dsRNA and 3C protease, are likely related to the primordial function of the NLRP1 inflammasome ( 19 ).…”

Section: Main Textmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted September 20, 2021. ; https://doi.org/10.1101/2021.09.20.461118 doi: bioRxiv preprint (rodents do not express CARD8) (13,18). As such, only DPP8/9 inhibitors, and not dsRNA and 3C protease, are likely related to the primordial function of the NLRP1 inflammasome (19).…”

mentioning

confidence: 99%

Oxidized thioredoxin-1 restrains the NLRP1 inflammasome

Ball

Wang

Warren

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

At least six human proteins detect danger-associated signals, assemble into complexes called inflammasomes, and trigger pyroptotic cell death. NLRP1 was the first protein discovered to form an inflammasome, but the danger signals and molecular mechanisms that control its activation have not yet been fully established. Here, we report that the NACHT-LRR region of NLRP1 directly binds to oxidized form of thioredoxin-1 (TRX1). We found that NLRP1 requires the ATPase activity of its NACHT domain to associate with TRX1, and that this interaction represses inflammasome activation. Moreover, we discovered that several patient-derived missense mutations in the NACHT-LRR region of NLRP1 weaken TRX1 binding, leading to inflammasome hyperactivation and autoinflammatory disease. Overall, our results establish that oxidized TRX1 binds to and restrains the NLRP1 inflammasome, thereby revealing a link between the cellular redox environment and innate immunity.

show abstract

“…These result show the poor conservation of the NLRP1 pathway between human and mouse skin [ 108 ]. Interestingly, 3C proteases and dsRNA only activate human NLRP1, whereas Anthrax Lethal Factor metalloprotease induces cleavage of murine Nlrp1b but not the human form [ 109 ]. T. gondii infection and Dpp8/9 inhibition with Talabostat (Val-boroPro) commonly activated both murine and human isoforms.…”

Section: The Nlrp Subfamilymentioning

confidence: 99%

Nod-Like Receptors in Host Defence and Disease at the Epidermal Barrier

Danis

Mellett

2021

IJMS

View full text Add to dashboard Cite

The nucleotide-binding domain and leucine-rich-repeat-containing family (NLRs) (sometimes called the NOD-like receptors, though the family contains few bona fide receptors) are a superfamily of multidomain-containing proteins that detect cellular stress and microbial infection. They constitute a critical arm of the innate immune response, though their functions are not restricted to pathogen recognition and members engage in controlling inflammasome activation, antigen-presentation, transcriptional regulation, cell death and also embryogenesis. NLRs are found from basal metazoans to plants, to zebrafish, mice and humans though functions of individual members can vary from species to species. NLRs also display highly wide-ranging tissue expression. Here, we discuss the importance of NLRs to the immune response at the epidermal barrier and summarise the known role of individual family members in the pathogenesis of skin disease.

show abstract

NLRP1: a jack of all trades, or a master of one?

Cited by 24 publications

References 12 publications

Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma

Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma

Oxidized thioredoxin-1 restrains the NLRP1 inflammasome

Nod-Like Receptors in Host Defence and Disease at the Epidermal Barrier

Contact Info

Product

Resources

About