Biology subjects

Stanton, C. R.

Publications and source records attributed to Stanton, C. R..

2 recordsLinked to original sources

bioRxiv2025

Optimizing PDIA1 Inhibition as a Strategy to Inhibit NLRP3 Inflammasome Activation and Activity

The NLRP3 inflammasome is a protein complex that promotes pro-inflammatory signaling as part of the innate immune response. Hyperactivation of the NLRP3 inflammasome has been implicated in many inflammatory and neurodegenerative diseases, leading to significant effort in developing strategies to limit its activation to intervene in these disorders. We previously showed that pharmacologic inhibition of the endoplasmic reticulum (ER)-localized protein disulfide isomerase PDIA1 suppresses NLRP3 activation and activity, identifying PDIA1 as a potential therapeutic target to mitigate hyperactive NLRP3 activity. Herein, we screen PDIA1 inhibitors to identify highly-potent compounds, including P1 and PACMA31, that pharmacologically target PDIA1 and block NLRP3 inflammasome assembly and activity. While sustained treatment with these PDIA1 inhibitors reduces THP1 viability, we show that acute treatment with these compounds is sufficient to both fully modify PDIA1 and inhibit NLRP3 inflammasome activity independent of any overt cellular toxicity. These results establish a treatment paradigm that can be exploited to develop highly-selective PDIA1 inhibitors to mitigate hyperactive NLRP3 inflammasome activity implicated in etiologically-diverse diseases.

biochemistry↗

bioRxiv2023

Pharmacologic Targeting of PDIA1 Inhibits NLRP3 Inflammasome Assembly and Activation

The NLRP3 inflammasome is a cytosolic protein complex that regulates innate immune signaling in response to diverse pathogenic insults through the proteolytic processing and secretion of pro-inflammatory cytokines such as IL-1{beta}. Hyperactivation of NLRP3 inflammasome signaling is implicated in the onset and pathogenesis of numerous diseases, motivating the discovery of new strategies to suppress NLRP3 inflammasome activity. We sought to define the potential for the proteostasis regulator AA147 to inhibit the assembly and activation of the NLRP3 inflammasome. AA147 is a pro-drug that is metabolically converted to a reactive metabolite at the endoplasmic reticulum (ER) membrane to covalently modify ER-localized proteins such as protein disulfide isomerases (PDIs). We show that AA147 inhibits NLRP3 inflammasome activity in monocytes and monocyte-derived macrophages through a mechanism involving impaired assembly of the active inflammasome complex. This inhibition is mediated through AA147-dependent covalent modification of PDIA1. Genetic depletion or treatment with other highly selective PDIA1 inhibitors similarly blocks NLRP3 inflammasome assembly and activation. Our results identify PDIA1 as a potential therapeutic target to mitigate NLRP3 inflammasome-mediated pro-inflammatory signaling implicated in etiologically diverse diseases.

cell biology↗