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KBTBD11，一种新型的 BTB-Kelch 蛋白，通过控制 Cullin3 介导的 NFATc1 泛素化来负调控破骨细胞的生成。

KBTBD11, a novel BTB-Kelch protein, is a negative regulator of osteoclastogenesis through controlling Cullin3-mediated ubiquitination of NFATc1.

机构信息

Department of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, 852-8588, Japan.

Department of Regenerative Oral Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, 852-8588, Japan.

出版信息

Sci Rep. 2019 Mar 5;9(1):3523. doi: 10.1038/s41598-019-40240-2.

DOI:10.1038/s41598-019-40240-2
PMID:30837587
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6401029/
Abstract

Kelch repeat and BTB domain-containing protein 11 (KBTBD11) is a member of the KBTBD subfamily of proteins that possess a BTB domain and Kelch repeats. Despite the presence of the Kbtbd11 gene in mammalian genomes, there are few reports about KBTBD11 at present. In this study, we identified the novel protein KBTBD11 as a negative regulator of osteoclast differentiation. We found that expression of KBTBD11 increased during osteoclastogenesis. Small-interfering-RNA-mediated knockdown of KBTBD11 enhanced osteoclast formation, and markedly increased the expression of several osteoclast marker genes compared with control cells. Conversely, KBTBD11 overexpression impaired osteoclast differentiation, and decreased the expression of osteoclast marker genes. Among six major signaling pathways regulating osteoclast differentiation, KBTBD11 predominantly influenced the nuclear factor of activated T cell cytoplasmic-1 (NFATc1) pathway. Mechanistically, KBTBD11 was found to interact with an E3 ubiquitin ligase, Cullin3. Further experiments involving immunoprecipitation and treatment with MG132, a proteasome inhibitor, showed that the KBTBD11-Cullin3 promotes ubiquitination and degradation of NFATc1 by the proteasome. Considering that NFATc1 is an essential factor for osteoclast differentiation, the KBTBD11 and Cullin3 probably regulate the levels of NFATc1 through the ubiquitin-proteasome degradation system. Thus, KBTBD11 negatively modulates osteoclast differentiation by controlling Cullin3-mediated ubiquitination of NFATc1.

摘要

Kelch 重复和 BTB 结构域蛋白 11（KBTBD11）是具有 BTB 结构域和 Kelch 重复的 KBTBD 蛋白亚家族的成员。尽管哺乳动物基因组中存在 Kbtbd11 基因，但目前关于 KBTBD11 的报道很少。在这项研究中，我们鉴定了新型蛋白 KBTBD11 是破骨细胞分化的负调节剂。我们发现 KBTBD11 的表达在破骨细胞发生过程中增加。小干扰 RNA 介导的 KBTBD11 敲低增强了破骨细胞的形成，并与对照细胞相比，显著增加了几个破骨细胞标记基因的表达。相反，KBTBD11 过表达损害了破骨细胞分化，并降低了破骨细胞标记基因的表达。在调节破骨细胞分化的六个主要信号通路中，KBTBD11 主要影响活化 T 细胞核因子细胞质 1（NFATc1）通路。从机制上讲，发现 KBTBD11 与 E3 泛素连接酶 Cullin3 相互作用。涉及免疫沉淀和用蛋白酶体抑制剂 MG132 处理的进一步实验表明，KBTBD11-Cullin3 通过蛋白酶体促进 NFATc1 的泛素化和降解。鉴于 NFATc1 是破骨细胞分化的必需因子，KBTBD11 和 Cullin3 可能通过泛素-蛋白酶体降解系统调节 NFATc1 的水平。因此，KBTBD11 通过控制 Cullin3 介导的 NFATc1 泛素化来负调节破骨细胞分化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/e787e8c7260c/41598_2019_40240_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/06aa0000a360/41598_2019_40240_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/d22f9d516f37/41598_2019_40240_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/3e9fc967db41/41598_2019_40240_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/eb7be6aa590f/41598_2019_40240_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/ad31270eba75/41598_2019_40240_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/0fa7c642103f/41598_2019_40240_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/7d8fa12c2186/41598_2019_40240_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/e787e8c7260c/41598_2019_40240_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/06aa0000a360/41598_2019_40240_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/d22f9d516f37/41598_2019_40240_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/3e9fc967db41/41598_2019_40240_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/eb7be6aa590f/41598_2019_40240_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/ad31270eba75/41598_2019_40240_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/0fa7c642103f/41598_2019_40240_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/7d8fa12c2186/41598_2019_40240_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/90ff/6401029/e787e8c7260c/41598_2019_40240_Fig8_HTML.jpg

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