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2024

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Chen Jiong/Nie Li/Wei Wenyi cooperation reveals the regulatory mechanism of NLRP3 membrane transport and inflammatory body activation!

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The activation of NLRP3 inflammasome is closely related to a variety of diseases and is required for cytokine secretion and thermal death under a variety of stimuli.Upon stimulation, NLRP3 undergoes subcellular membrane transport and conformational rearrangement for inflammasome inMicrotubule Tissue Center(MTOC) assembly ready.

August 21, 2024, Ningbo University, Chen Jiong,Nie Li,Wei Wenyi of Harvard University in the United StatesMolecular Cell（IF=14.5）Published online entitled"Consecutive palmitoylation and phosphorylation orchestrates NLRP3 membrane trafficking and inflammasome activation"'s research paper,The study showedSequential palmitoylation and phosphorylation coordinate NLRP3 membrane trafficking and inflammasome activation.

Here, the researchers used human and mouse cells to elucidate the coordination mechanisms behind these ordered processes. Specifically, NLRP3 undergoes palmitoylation at two sites of the palmitoyltransferase zDHHC1, facilitating its transport between subcellular membranes, including mitochondria, trans-Golgi network (TGN) andendosome. This dynamic transport ultimately leads to the localization of NLRP3 to MTOC, where LATS1/2 is pre-recruited to MTOC during priming, phosphorylating NLRP3, further facilitating its interaction with nima-associated kinase 7 (NEK7), and ultimately leading to full activation of NLRP3. Consistent with this, the lackZdhhc1can mitigateLPSinduced inflammation and protected the mice from death.In conclusion, this study provides valuable insights into the regulation of NLRP3 membrane trafficking and inflammasome activation, which are controlled by palmitoylation and phosphorylation events.

NACHT-, leucine-rich repeat (LRR)-and pyrin domain (PYD)-containing protein 3 (NLRP3), a member of the NOD-like receptor (NLR) family, is an upstream sensor of activation of the NLRP3 inflammasome. The typical NLRP3 inflammasome is activated in two steps. First, the priming step results in an inflammasome component and NLRP3. Transcriptional upregulation of post-translational protein modifications; secondly, activation steps, stimulated by a variety of pathogenic and injury-related signals, such as pore-forming toxins (e. g., nigericin and gramicidin a), extracellular ATP, and particulate matter, initiate the assembly and caspase-activation of the inflammasome.Activated caspase-1 in turn cleaves interleukin (IL)-1β. pro-IL-18 and GSDMD, leading to pore formation, cytokine release, and pyroptosis.

The assembly and activation of the NLRP3 inflammasome is a tightly regulated process whose dysregulation is associated with a variety of inflammatory diseases, including metabolic disorders, central nervous system diseases and cancer. Remarkably, increasing evidence highlights the importance of membrane transport for NLRP3 activation. NLRP3 localizes to the cytoplasm and cell membrane before activation. Once stimulated, NLRP3 passes through a dispersed trans-Golgi network (TGN) pathway to mitochondria and then to the microtubule organizing center (MTOC).In addition, a recent study also linked NLRP3 to endosomes, showing that the TGN protein-containing vesicles are actually endosomes, further suggesting thatThe importance and complexity of membrane transport in the timely regulation of NLRP3 inflammasome activation.

While the exact mechanism of subcellular trafficking of NLRP3 is unknown, it has been proposed that palmitoylation of proteins catalyzed by palmitoyltransferase (Zdhhc) can localize and transport proteins within the membrane. Therefore, whether palmitoylation is involved in NLRP3 membrane transport is worth exploring.Remarkably, during membrane transport, NLRP3 remained sequestered in an inactive "cage" structure, preventing the inclusioncaspaseRecruitment of apoptosis-associated dot-like proteins of the recruitment domain (ASC) and assembly of the following NLRP3 inflammasomes.Thus, the key subsequent event conferring full activation of NLRP3 involves its interaction with MTOC-localized non-mitotic A (NIMA)-associated kinase 7 (NEK7), thereby opening the inactive NLRP3 cage. However, the LRR domain of NLRP3 in the cage-like structure blocks the pathway of NEK7, and how NLRP3 interacts with NEK7 is still poorly understood.
In this study, the authors found that NLRP3 undergoes sequential palmitoylation on C958 and C130 (mouse equivalent: C955 and C126) during initiation and activation, directing it to specific membranes and eventually to MTOC.At the same time, large tumor suppressor kinase 1 and 2 (LATS1/2)30 is scheduled to be located in MTOC at the start-up stage, waiting for the Ser265 site of NLRP3 (mouse equivalent site: S261) of phosphorylated translocation for NEK7 interaction.These findings reveal the mechanism of sequential palmitoylation and phosphorylation events in fine-tuning NLRP3 subcellular trafficking and activation, which has important implications for the potential treatment of inflammatory diseases associated with NLRP3 dysregulation.

 

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An efficient cfDNA whole genome sequencing technology AccuScan by Hu Zhiqian and other teams of Tongji University, which can perform whole genome error correction at a single read level!

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