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HECTD3 通过阻断 NLRP3-NEK7 相互作用抑制 NLRP3 炎性小体的组装和激活。

HECTD3 inhibits NLRP3 inflammasome assembly and activation by blocking NLRP3-NEK7 interaction.

机构信息

Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China.

Kunming College of Life Sciences, University of Chinese Academy Sciences, Kunming, 650204, China.

出版信息

Cell Death Dis. 2024 Jan 24;15(1):86. doi: 10.1038/s41419-024-06473-4.

DOI:10.1038/s41419-024-06473-4
PMID:38267403
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10808187/
Abstract

The NLRP3 inflammasome plays an important role in protecting the host from infection and aseptic inflammation, and its regulatory mechanism is not completely understood. Dysregulation of NLRP3 can cause diverse inflammatory diseases. HECTD3 is a E3 ubiquitin ligase of the HECT family that has been reported to participate in autoimmune and infectious diseases. However, the relationship between HECTD3 and the NLRP3 inflammasome has not been well studied. Herein, we show that HECTD3 blocks the interaction between NEK7 and NLRP3 to inhibit NLRP3 inflammasome assembly and activation. In BMDMs, Hectd3 deficiency promotes the assembly and activation of NLRP3 inflammasome and the secretion of IL-1β, while the overexpression of HECTD3 inhibits these processes. Unexpectedly, HECTD3 functions in an E3 activity independent manner. Mechanically, the DOC domain of HECTD3 interacts with NACHT/LRR domain of NLRP3, which blocks NLRP3-NEK7 interaction and NLRP3 oligomerization. Furthermore, HECTD3 inhibits monosodium urate crystals (MSU)-induced gouty arthritis, a NLRP3-related disease. Thus, we reveal a novel regulatory mechanism of NLRP3 by HECTD3 and suggest HECTD3 could be a potential therapeutic target for NLRP3-dependent pathologies.

摘要

NLRP3 炎性小体在宿主抗感染和无菌性炎症中发挥着重要作用，但其调控机制尚不完全清楚。NLRP3 的失调可导致多种炎症性疾病。HECTD3 是一种 HECT 家族的 E3 泛素连接酶，已被报道参与自身免疫和感染性疾病。然而，HECTD3 与 NLRP3 炎性小体之间的关系尚未得到很好的研究。在此，我们发现 HECTD3 可阻断 NEK7 与 NLRP3 的相互作用，从而抑制 NLRP3 炎性小体的组装和激活。在 BMDMs 中，Hectd3 缺陷促进 NLRP3 炎性小体的组装和激活以及 IL-1β 的分泌，而 HECTD3 的过表达则抑制这些过程。出乎意料的是，HECTD3 以一种非 E3 活性依赖的方式发挥作用。在机制上，HECTD3 的 DOC 结构域与 NLRP3 的 NACHT/LRR 结构域相互作用，从而阻断 NLRP3-NEK7 相互作用和 NLRP3 寡聚化。此外，HECTD3 抑制单钠尿酸盐晶体（MSU）诱导的痛风性关节炎，这是一种 NLRP3 相关疾病。因此，我们揭示了 HECTD3 对 NLRP3 的一种新的调控机制，并提示 HECTD3 可能是 NLRP3 依赖性病理的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d369/10808187/f53211e46b80/41419_2024_6473_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d369/10808187/3b6361855611/41419_2024_6473_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d369/10808187/eba7eb3595db/41419_2024_6473_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d369/10808187/d45ec2b74591/41419_2024_6473_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d369/10808187/eb5f862f8ebc/41419_2024_6473_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d369/10808187/ae804f142f27/41419_2024_6473_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d369/10808187/f53211e46b80/41419_2024_6473_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d369/10808187/3b6361855611/41419_2024_6473_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d369/10808187/eba7eb3595db/41419_2024_6473_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d369/10808187/d45ec2b74591/41419_2024_6473_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d369/10808187/eb5f862f8ebc/41419_2024_6473_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d369/10808187/ae804f142f27/41419_2024_6473_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d369/10808187/f53211e46b80/41419_2024_6473_Fig6_HTML.jpg

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