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gasdermin D 的棕榈酰化将其导向细胞焦亡过程中的膜转位和孔形成。

The palmitoylation of gasdermin D directs its membrane translocation and pore formation during pyroptosis.

机构信息

Department of Pathology, Dana-Farber/Harvard Cancer Center, Harvard Medical School and Department of Laboratory Medicine, Boston Children's Hospital, Enders Research Building, Room 811, Boston, MA 02115, USA.

Biomedical Mass Spectrometry and Systems Biology, University of Southern Denmark, Odense, Denmark.

出版信息

Sci Immunol. 2024 Apr 12;9(94):eadn1452. doi: 10.1126/sciimmunol.adn1452.

DOI:10.1126/sciimmunol.adn1452
PMID:38530158
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11367861/
Abstract

Plasma membrane perforation elicited by caspase cleavage of the gasdermin D (GSDMD) N-terminal domain (GSDMD-NT) triggers pyroptosis. The mechanisms underlying GSDMD membrane translocation and pore formation are not fully understood. Here, using a proteomic approach, we identified fatty acid synthase (FASN) as a GSDMD-binding partner. S-palmitoylation of GSDMD at Cys/Cys (human/mouse), catalyzed by palmitoyl acyltransferases ZDHHC5 and ZDHHC9 and facilitated by reactive oxygen species (ROS), directly mediated membrane translocation of GSDMD-NT but not full-length GSDMD (GSDMD-FL). Palmitoylation of GSDMD-FL could be induced before inflammasome activation by stimuli such as lipopolysaccharide (LPS), consequently serving as an essential molecular event in macrophage priming. Inhibition of GSDMD palmitoylation suppressed macrophage pyroptosis and IL-1β release, mitigated organ damage, and enhanced the survival of septic mice. Thus, GSDMD-NT palmitoylation is a key regulatory mechanism controlling GSDMD membrane localization and activation, which may offer an additional target for modulating immune activity in infectious and inflammatory diseases.

摘要

由半胱天冬酶切割gasdermin D（GSDMD）N 端结构域（GSDMD-NT）引发的质膜穿孔触发细胞焦亡。GSDMD 膜易位和孔形成的机制尚未完全阐明。在这里，我们使用蛋白质组学方法鉴定了脂肪酸合酶（FASN）是 GSDMD 的结合伴侣。由 ZDHHC5 和 ZDHHC9 催化的 Cys/Cys（人/鼠）上的 GSDMD S-棕榈酰化，通过活性氧（ROS）促进，直接介导 GSDMD-NT 但不是全长 GSDMD（GSDMD-FL）的膜易位。GSDMD-FL 的棕榈酰化可以在炎症小体激活之前被刺激（如脂多糖（LPS））诱导，因此作为巨噬细胞启动的必需分子事件。GSDMD 棕榈酰化的抑制抑制了巨噬细胞细胞焦亡和 IL-1β 的释放，减轻了器官损伤，并提高了脓毒症小鼠的存活率。因此，GSDMD-NT 棕榈酰化是控制 GSDMD 膜定位和激活的关键调节机制，这可能为调节感染和炎症性疾病中的免疫活性提供了另一个靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/a15c212218e7/nihms-2014239-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/e6e697e6557a/nihms-2014239-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/760034d149af/nihms-2014239-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/9175154095c0/nihms-2014239-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/dc25952b48fb/nihms-2014239-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/404afdab7822/nihms-2014239-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/e0afa300899f/nihms-2014239-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/a15c212218e7/nihms-2014239-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/e6e697e6557a/nihms-2014239-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/760034d149af/nihms-2014239-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/9175154095c0/nihms-2014239-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/dc25952b48fb/nihms-2014239-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/404afdab7822/nihms-2014239-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/e0afa300899f/nihms-2014239-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6ebe/11367861/a15c212218e7/nihms-2014239-f0007.jpg

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Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury.
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