Fig. 4
From: Role of inflammasomes in multiple sclerosis and their potential as therapeutic targets
Modulation of NLRP3 signaling pathways. Upon stimulation, the tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD) forms a complex in which receptor-interacting protein 1 (RIP1) acquires a polyubiquitin chain. Transforming growth factor beta-activated kinase 1 (TAK1, also known as mitogen-activated protein kinase kinase kinase 7 (MAP3K7)) binds to the polyubiquitin chain and activates the IκB kinase (IKK) complex (IKKα/IKKβ/NEMO (NF-kappa-B essential modulator)), leading to the activation of NF-κB. TAK1 also activates MAP kinases (MAPK) that activate the transcription factor, activator protein 1 (AP-1). NF-κB and AP-1 induce expression of inflammatory cytokines and antiapoptotic proteins. Inhibition of TAK1 promotes the assembly of the Panoptotic cell death complex. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in association with Fs7-associated cell surface antigen (Fas)-associated death domain (FADD) and caspase-8 (Casp8) triggers nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome leading to activation of caspase-1 (CASP1) and cleavage of pro-interleukin (IL)-1β and pro-IL-18 into mature cytokines and caspase-1-mediated cleavage of Gasdermin D (GSDMD) resulting in release of IL-1β, IL-18, and apoptosis speck-like staining protein containing a CARD domain (ASC) specks. DEAD-box helicase 3 X-linked (DDX3X) promotes NLRP3 inflammasome activation and the pro-death cell-fate decision by interacting with the NLRP3 NACHT domain through its helicase (Heli) domain. Induction of stress granules causes the sequestration of DDX3X making it unavailable for NLRP3 inflammasome activation and thereby leading to a pro-survival state. Serine/threonine-protein kinase NEK7 interacts with the NACHT domain of NLRP3 inducing NLRP3 activation. NLRP3 is also activated by potassium efflux mediated by two-pore domain K+ (TWIK2) and voltage-gated potassium channel (Kv1.3) and pannexin1 (Panx1).