1The intracellular cysteine protease caspase-1 is critically involved in obesity-induced inflammation 2 in adipose tissue. A substantial body of evidence from immune cells, such as macrophages, has 3shown that caspase-1 activation depends largely on a protein complex, called the NLRP3 4 inflammasome, which consists of the NOD-like receptor (NLR) family protein NLRP3, the adaptor 5 protein ASC, and caspase-1 itself. However, it is not fully understood how caspase-1 activation is 6 regulated within adipocytes upon inflammatory stimuli. In this study, we show that TNF-α-induced 7 activation of caspase-1 is accompanied by robust induction of NLRP3 in 3T3-L1 adipocytes but that 8 caspase-1 activation may not depend on the NLRP3 inflammasome. Treatment of 3T3-L1 cells with 9 TNF-α induced mRNA expression and activation of caspase-1. Although the basal expression of 10 NLRP3 and ASC was undetectable in unstimulated cells, TNF-α strongly induced NLRP3 11 expression but did not induce ASC expression. Interestingly, inhibitors of the ERK MAP kinase 12 pathway strongly suppressed NLRP3 expression but did not suppress the expression and activation 13 of caspase-1 induced by TNF-α, suggesting that NLRP3 is dispensable for TNF-α-induced 14 caspase-1 activation. Moreover, we did not detect the basal and TNF-α-induced expression of other 15 NLR proteins (NLRP1a, NLRP1b, and NLRC4), which do not necessarily require ASC for 16 caspase-1 activation. These results suggest that TNF-α induces caspase-1 activation in an 17 inflammasome-independent manner in 3T3-L1 cells and that the ERK-dependent expression of 18
PGAM5 is a unique type of protein phosphatase that exists in mitochondria. It has been shown to exist in the inner mitochondrial membrane through its transmembrane domain and to be cleaved within the transmembrane domain upon mitochondrial dysfunction. However, its submitochondrial localization remains controversial; many researchers claim that PGAM5 localizes to the outer mitochondrial membrane based on the findings that PGAM5 associates with many cytoplasmic proteins. Here, we found that cleaved PGAM5 was released from mitochondria during mitophagy, a selective form of autophagy specific for mitochondria, and that the release was inhibited by proteasome inhibitors in HeLa cells stably expressing the E3 ubiquitin ligase Parkin. However, treatment of parental HeLa cells lacking Parkin with mitophagy-inducing agents caused PGAM5 cleavage but did not cause its release from mitochondria. Thus, cleaved PGAM5 appears to be released from mitochondria depending on proteasome-mediated rupture of the outer membrane during mitophagy, which has been previously shown to precede autophagy-mediated degradation of whole mitochondria. This study suggests that PGAM5 senses mitochondrial dysfunction in the inner mitochondrial membrane and serves as a signaling intermediate that regulates the cellular response to mitochondrial stress upon its cleavage and release from mitochondria.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.