NLRP1 inflammasome modulates senescence and senescence-associated secretory phenotype

Abstract

Senescence is a cellular aging-related process triggered by different stresses and characterized by the secretion of various inflammatory factors referred to as the senescence-associated secretory phenotype (SASP). Here, we present evidence that the inflammasome sensor, NLRP1, is a key mediator of senescence induced by irradiation both in vitro and in vivo. The NLRP1 inflammasome promotes senescence by regulating the expression of p16, p21, p53, and SASP in Gasdermin D (GSDMD)-dependent manner as these responses are reduced in conditions of NLRP1 insufficiency or GSDMD inhibition. Mechanistically, the NLRP1 inflammasome is activated downstream of the cytosolic DNA sensor cGMP-AMP (cGAMP) synthase (cGAS) in response to genomic damage. These findings provide a rationale for inhibiting the NLRP1 inflammasome-GSDMD axis to treat senescence-driven disorders.

Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells

“…Among the genes that negatively correlated with cancer progression in the RA signaling and downstream target signatures, we found MAOB, ESR1, and PTGS2, which also control cellular senescence. 34 , 35 Between the genes related to RA metabolism, we found ALDH1A2 and ALDH1A3 that control the conversion of retinal to RA ( Figures 2 F and S2D–S2J ). To assess whether adapalene treatment could activate the RA pathways in prostate tumor cells, we took advantage of PC3 cells that exhibit a decreased RA signaling compared to normal cells ( Figure S2 C).…”

NLRP3 and NLRP1/CARD8 pathways differently contribute to pyroptosis of CD8+ T cells of ART-treated HIV patients

“…The copyright holder for this preprint this version posted May 16, 2023. ; https://doi.org/10.1101/2023.05.15.540712 doi: bioRxiv preprint 14 hand, it is still discussed whether cell stress, namely ER stress (D'Osualdo et al 2015;Cao et al, 2019), reductive stress (Wang et al, 2023), or protein folding stress (Orth et al, 2023), or even senescence it-self (Muela-Zarzuela et al, 2023) can activate NLRP1 and/or CARD8 inflammasome.…”

Emerging Role of GCN1 in Disease and Homeostasis

“…Thus, prolonged collisions by bulky adducts triggered by UV light B (UVB), 4-nitroquinoline, or mitomycin C activate RSR and cause G2/M cell-cycle arrest [ 79 ]. Furthermore, ZAKα activates the human Nod-like receptor 1 (NRLP1) [ 95 ], which was recently shown to be involved in senescence [ 96 ]. Consistently, ZAKα mediates oxidative stress-mediated induction of SAPK activation [ 97 ].…”