Inflammasome Meets Centrosome: Understanding the Emerging Role of Centrosome in Controlling Inflammasome Activation

Abstract

Inflammasomes are multi-protein platforms that are assembled in response to microbial and danger signals to activate proinflammatory caspase-1 for production of active form of IL-1β and induction of pyroptotic cell death. Where and how an inflammasome is assembled in cells has remained controversial. While the endoplasmic reticulum, mitochondria and Golgi apparatus have been reported to be associated with inflammasome assembly, none of these sites seems to match the morphology, number and size of activated inflammasomes that are microscopically observable as one single perinuclear micrometer-sized punctum in each cell. Recently, emerging evidence shows that NLRP3 and pyrin inflammasomes are assembled, activated and locally regulated at the centrosome, the major microtubule organizing center in mammalian cells, elegantly accounting for the singularity, size and perinuclear location of activated inflammasomes. These new exciting findings reveal the previously unappreciated importance of the centrosome in controlling inflammasome assembly and activation as well as inflammasome-related diseases.

Endosomal Trafficking of Two Pore K+Efflux Channel TWIK2 to Plasmalemma Mediates NLRP3 Inflammasome Activation and Inflammatory Injury

“…Double-ring caged NLRP3 is recruited to the dispersed TGN (dTGN) through ionic bonding between its conserved polybasic region and negatively charged phosphatidylinositol-4-phosphate (PtdIns4P) on the dTGN. dTGNvs serve as a scaffold for NLRP3 aggregation into multiple puncta, leading to polymerization of the adaptor protein ASC, and thereby activating the downstream signaling cascade 13 These results suggest a physiological NLRP3 oligomer on the membrane poised to sense diverse signals to induce inflammasome activation 9 Evidence also shows that NLRP3 inflammasome is assembled and activated at the centrosome 14–17 , the major microtubule organizing center in mammalian cells, accounting for the singularity, size, and perinuclear location of activated inflammasomes 14 However, little is known about the triggers at the plasma membrane initiating the downstream assembly and activation of NLRP3 complex.…”

“…These results suggest a physiological NLRP3 oligomer on the membrane poised to sense diverse signals to induce inflammasome activation 9 . Evidence also shows that NLRP3 inflammasome is assembled and activated at the centrosome [14][15][16][17] , the major microtubule organizing center in mammalian cells, accounting for the singularity, size, and perinuclear location of activated inflammasomes 14 . However, little is known about the triggers at the plasma membrane initiating the downstream assembly and activation of NLRP3 complex.…”

“…Several studies have elucidated the structure and assembly mechanisms of the NLRP3 complex. The inactive NLRP3 form (doublering cages of NLRP3) is predominantly membrane associated (such as endoplasmic reticulum -ER, mitochondria and Golgi Apparatus) and is recruited, assembled and activated at the centrosome [9][10][11][12][13][14][15][16][17] .…”

An Alkaline Nanocage Continuously Activates Inflammasomes by Disrupting Multiorganelle Homeostasis for Efficient Pyroptosis

“…26−28 Under normal conditions, ER−endosome membrane contact sites (EECS) inhibit the recruitment and subsequent transfer of the NLRP3 inflammasome to the centrosome by the endosome. 12,29 Disturbing EECS by inducing ER stress can enhance NLRP3 inflammasome activation, increasing the potential to induce pyroptosis. 12,30,31 However, lysosome-associated autophagy can alleviate ER stress by degrading the stressed ER.…”

Exosomes derived from heat shock preconditioned bone marrow mesenchymal stem cells alleviate cisplatin-induced ototoxicity in mice

“…NOD-leucine-rich repeat and pyrin-containing protein 3 (NLRP3) inflammasome is a vital player in inflammation or innate immunity, comprising NLRP3, apoptosis-associated speck-like protein (ASC), and pro-caspase-1, which sensors microbes or damage-associated molecular patterns to regulate the activation of caspase-1-dependent release of interleukin (IL)-1β and IL-18 [ 10 , 19 ]. Heat shock protein 70 (HSP70) can directly interact with NLRP3 to prohibit the activation of NLRP3 inflammasome [ 1 ].…”