E3 泛素连接酶 TRIM21 负调控细胞内双链 DNA 的固有免疫反应。
The E3 ubiquitin ligase TRIM21 negatively regulates the innate immune response to intracellular double-stranded DNA.
机构信息
Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, Texas, USA.
出版信息
Nat Immunol. 2013 Feb;14(2):172-8. doi: 10.1038/ni.2492. Epub 2012 Dec 9.
Abstract
DDX41 is a sensor of intracellular double-stranded DNA (dsDNA) in myeloid dendritic cells (mDCs) that triggers a type I interferon response via the signaling adaptor STING. We identified the E3 ligase TRIM21 as a DDX41-interacting protein and found that knockdown of or deficiency in TRIM21 resulted in enhanced type I interferon responses to intracellular dsDNA and DNA viruses. Overexpression of TRIM21 resulted in more degradation of DDX41 and less production of interferon-β (IFN-β) in response to intracellular dsDNA. The SPRY-PRY domain of TRIM21 interacted with the DEADc domain of DDX41. Lys9 and Lys115 of DDX41 were the targets of TRIM21-mediated ubiquitination. TRIM21 is therefore an interferon-inducible E3 ligase that induces the Lys48 (K48)-linked ubiquitination and degradation of DDX41 and negatively regulates the innate immune response to intracellular dsDNA.
摘要
DDX41 是髓系树突状细胞（mDCs）中细胞内双链 DNA（dsDNA）的传感器，通过信号适配器 STING 触发 I 型干扰素反应。我们鉴定出 E3 连接酶 TRIM21 是 DDX41 的相互作用蛋白，并发现 TRIM21 的敲低或缺失导致对细胞内 dsDNA 和 DNA 病毒的 I 型干扰素反应增强。TRIM21 的过表达导致细胞内 dsDNA 反应中 DDX41 的降解更多，干扰素-β（IFN-β）的产生更少。TRIM21 的 SPRY-PRY 结构域与 DDX41 的 DEADc 结构域相互作用。DDX41 的赖氨酸 9 和赖氨酸 115 是 TRIM21 介导的泛素化的靶标。因此，TRIM21 是一种干扰素诱导的 E3 连接酶，可诱导 DDX41 的 Lys48（K48）连接泛素化和降解，并负调控对细胞内 dsDNA 的固有免疫反应。
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