TRIM21 as a regulator of UVB- and cytosolic DNA-driven IFN responses in lupus

系统性红斑狼疮（SLE）患者暴露于紫外线下会产生光敏性 (UV)通常会导致狼疮发作，引发关节疼痛和疲劳等症状， 病变然而，尽管将UVB暴露与全身效应联系起来的机制尚不清楚，但I型干扰素 在其中扮演着重要角色我们以前的工作表明，E3连接酶TRIM 21是IFN的负调节因子， 表情有趣的是，我们观察到Trim 21-/-小鼠对DNA的反应是自发的皮肤病变， 皮肤中的检测。这促使我们研究Trim 21-/-小鼠是否对紫外线过敏， 导致皮肤发炎Trim 21-/-小鼠对UVB的反应更严重， 以及脾肿大和全身IFN水平升高。关于TRIM 21的目标， 调节UVB诱导的反应，我们已经确定了DDX 41，一个相对研究不足的DNA传感器， 潜在目标我们假设TRIM 21通过预防全身性疾病而起到守门人的作用。 由细胞溶质DNA传感驱动的不受控制的系统性IFN应答，例如在UVB皮肤中证实的 模型，这可能对SLE的光敏性有影响。为了评估这一点，我们提出以下建议： 目的1：评估TRIM 21在UVB诱导的皮肤炎症中的作用以及它如何促进全身炎症反应。 变化我们将定义哪些免疫细胞是Trim 21-/-小鼠全身性疾病的关键，以及STING- IFN依赖性和非依赖性途径介导了从局部到全身的转变 在不存在TRIM 21的情况下，响应UVB的炎症。 目的2：确定TRIM 21和DDX 41在响应UVB的cGAS-STING信号传导中的调节作用。 我们将研究TRIM 21和DDX 41是如何在UVB下游调节的，并询问它们的损失如何改变UVB的活性。 使用生物化学和蛋白质组学的组合来研究STING信号体的组成、稳定性和功能。 目的3：定义TRIM 21的丢失如何促进皮肤和全身UVB驱动的IFN应答。 对SLE患者的PBMC和皮肤活检的分析将确定TRIM 21如何有助于SLE的发生。 SLE中的光敏性以及STING在驱动这些反应中的作用。 影响：本项目将确定TRIM 21迄今为止未知的作用的机制， 控制UVB驱动的系统性IFN应答，并询问改变的TRIM 21调节途径是否可以 解释UVB暴露与SLE患者狼疮发作风险增加之间的联系。

Patients with systemic lupus erythematosus (SLE) experience photosensitivity, with exposure to ultraviolet light (UV) often driving lupus flares, triggering symptoms like joint pain and fatigue, in addition to causing cutaneous lesions. However, although the mechanism(s) linking UVB exposure to systemic effects are unclear, type I IFNs are known to play a role. Our previous work has shown that the E3 ligase TRIM21 is a negative regulator of IFN expression. Interestingly we observed that Trim21-/- mice develop spontaneous skin lesions in response to DNA detection in the skin. This prompted us to investigate whether Trim21-/- mice were hyperresponsive to UV in driving skin inflammation. Trim21-/- mice develop more severe skin inflammation in response to UVB compared to wild type, as well as splenomegaly and enhanced levels of systemic IFNs. Regarding targets for TRIM21 in regulating UVB-induced responses we have identified DDX41, a relatively under studied DNA sensor as a potential target. We hypothesize that TRIM21 acts as a gatekeeper against systemic disease by preventing uncontrolled systemic IFN responses driven by cytosolic DNA sensing, such as demonstrated in the UVB skin model and that this may have implications for photosensitivity in SLE. To evaluate this, we propose the following: Aim 1: Assess the role of TRIM21 in UVB-induced skin inflammation and how it contributes to systemic changes. We will define what immune cells are key to systemic disease in the Trim21-/- mice and how STING- and IFN-dependent and independent pathways mediate the drive the transition from local to systemic inflammation in response to UVB in the absence of TRIM21. Aim 2: Determine the role of TRIM21 and DDX41 in regulating cGAS-STING signaling in response to UVB. We will investigate how TRIM21 and DDX41 is regulated downstream of UVB and ask how their loss alters the composition, stability and function of the STING signalsome using a combination of biochemistry and proteomics. Aim 3: Define how loss of TRIM21 contributes both cutaneous and systemic UVB-driven IFN responses. Analysis of PBMCs and skin biopsies from SLE patients will determine how TRIM21 may contribute to photosensitivity in SLE and the role of STING in driving these responses. Impact: This project will determine the mechanisms underlying this hitherto unknown role of TRIM21 in controlling UVB-driven systemic IFN responses and ask whether altered TRIM21-regulated pathways can explain the link between UVB exposure and increased risk of lupus flare in SLE.