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河马蛋白激酶Cζ-核因子κB信号轴：软骨细胞对机械应力反应的可药物调控因子

Hippo-PKCζ-NFκB signaling axis: A druggable modulator of chondrocyte responses to mechanical stress.

作者信息

Cai Xiaomin, Warburton Christopher, Perez Olivia F, Wang Ying, Ho Lucy, Finelli Christina, Ehlen Quinn T, Wu Chenzhou, Rodriguez Carlos D, Kaplan Lee, Best Thomas M, Huang Chun-Yuh, Meng Zhipeng

机构信息

Department of Molecular and Cellular Pharmacology, Miller School of Medicine, Miami, FL, USA.

Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.

出版信息

iScience. 2024 May 15;27(6):109983. doi: 10.1016/j.isci.2024.109983. eCollection 2024 Jun 21.

DOI:10.1016/j.isci.2024.109983
PMID:38827404
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11140209/
Abstract

Recent studies have implicated a crucial role of Hippo signaling in cell fate determination by biomechanical signals. Here we show that mechanical loading triggers the activation of a Hippo-PKCζ-NFκB pathway in chondrocytes, resulting in the expression of NFκB target genes associated with inflammation and matrix degradation. Mechanistically, mechanical loading activates an atypical PKC, PKCζ, which phosphorylates NFκB p65 at Serine 536, stimulating its transcriptional activation. This mechanosensitive activation of PKCζ and NFκB p65 is impeded in cells with gene deletion or chemical inhibition of Hippo core kinases LATS1/2, signifying an essential role of Hippo signaling in this mechanotransduction. A PKC inhibitor AEB-071 or PKCζ knockdown prevents p65 Serine 536 phosphorylation. Our study uncovers that the interplay of the Hippo signaling, PKCζ, and NFκB in response to mechanical loading serves as a therapeutic target for knee osteoarthritis and other conditions resulting from mechanical overloading or Hippo signaling deficiencies.

摘要

最近的研究表明， Hippo信号通路在生物力学信号决定细胞命运中起关键作用。在此，我们发现机械负荷可触发软骨细胞中Hippo-PKCζ-NFκB信号通路的激活，导致与炎症和基质降解相关的NFκB靶基因表达。机制上，机械负荷激活非典型蛋白激酶C（PKC）PKCζ，其使NFκB p65的丝氨酸536位点磷酸化，刺激其转录激活。在基因缺失或化学抑制Hippo核心激酶LATS1/2的细胞中，PKCζ和NFκB p65的这种机械敏感性激活受到阻碍，表明Hippo信号通路在这种机械转导中起重要作用。PKC抑制剂AEB-071或PKCζ敲低可阻止p65丝氨酸536位点磷酸化。我们的研究发现，Hippo信号通路、PKCζ和NFκB在对机械负荷的反应中的相互作用可作为膝骨关节炎和其他由机械过载或Hippo信号通路缺陷导致的疾病的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/72b940727be9/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/1f5dafcb7206/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/f9920bac0425/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/1776ac92143c/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/afe67409c88a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/d4b9560498f9/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/ab992044e3e0/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/a0feec68e35a/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/72b940727be9/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/1f5dafcb7206/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/f9920bac0425/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/1776ac92143c/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/afe67409c88a/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/d4b9560498f9/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/ab992044e3e0/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/a0feec68e35a/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db94/11140209/72b940727be9/gr7.jpg

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