Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome

Abstract

The NLRP3 inflammasome can be activated by diverse stimuli, including nigericin, uric acid crystals, amyloid-β fibrils, and extracellular ATP. The mitotic kinase NEK7 licenses NLRP3 inflammasome assembly and activation in the interphase. Here we report a 3.8-Å cryo-electron microscopy structure of inactive human NLRP3 in complex with NEK7. The earring-shaped Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

BTK operates a phospho-tyrosine switch to regulate NLRP3 inflammasome activity

“…1E, Ref. (8) and Methods). We next tested whether BTK is able to phosphorylate NLRP3 upon nigericin treatment.…”

“…Inflammation mediated via the NLRP3 inflammasome supports the resolution of infections and sterile insults but also contributes to pathology in multiple human diseases such as Cryopyrin-associated periodic fever syndromes (CAPS), gout, stroke or Alzheimer’s disease, and atherosclerosis (10, 11) . Thus, the activity of the NLRP3 inflammasome, a molecular machine maturing IL-1 family cytokines via the activity of caspase-1, is tightly controlled at several levels: At the structural level, recent cryo-EM studies demonstrated that the 3D conformation of NLRP3 is critical for NLRP3 oligomerization and may depend on ADP/ATP binding (8) . In addition, NLRP3 binding proteins, such as NEK7, have been shown to have an impact on inflammasome activity (3, 12) .…”

“… Abstract Inflammation is required for host defense as well as wound healing but wields enormous destructive potential, highlighting the need for multiple ‘checks and balances’ (1) . The NLRP3 inflammasome, a pivotal molecular machine for the maturation of IL-1 family pro-inflammatory cytokines (1) , is controlled by accessory proteins (2, 3) , post-translational modifications (4, 5) , localization (6, 7) and oligomerization (8) . How these factors act in concert is unclear.…”

Priming enables a NEK7-independent route of NLRP3 activation

“…Based on the redundancy between TAK1 and NEK7 in facilitating NLRP3 inflammasome activation, we conclude that NEK7 serves as a priming factor of the NLRP3 inflammasome. In line with this notion, recent structural evidence suggests that NEK7 functions to stabilize individual NLRP3 molecules in a semi-open, but not fully active conformation (Sharif et al, 2019).…”

“…In this regard, it has been suggested that NEK7 is employed for NLRP3 activation in order to avoid inflammasome formation during mitosis, when NEK7 is not available . Indeed, it has been speculated that the cellular perturbation immediately upstream of NLRP3 commonly occurs during mitosis and thus the dependency on NEK7 prevents inadvertent inflammasome activation during cell division (Sharif et al, 2019). However, the here-uncovered redundancy of NEK7 priming with other cell cycle-independent priming pathways (e.g.…”