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

系统性红斑狼疮(SLE)患者对紫外线有光敏反应 (紫外线)经常导致红斑狼疮，除了引起皮肤外，还会引发关节疼痛和疲劳等症状 损伤。然而，尽管UVB暴露与全身效应之间的联系机制(S)尚不清楚，但I型IFN 都是已知起到一定作用的。我们以前的工作表明，E3连接酶TRIM21是干扰素的负调控因子 表情。有趣的是，我们观察到Trim21-/-小鼠对DNA产生自发性皮肤损伤 皮肤中的检测。这促使我们调查Trim21-/-小鼠是否对紫外线具有高反应性 导致皮肤发炎。与UVB相比，Trim21-/-小鼠出现更严重的皮肤炎症反应 至野生型，以及脾肿大和全身性IFN水平升高。关于TRIM21年的目标 调控UVB诱导的反应我们已经鉴定出DDX41，一个相对研究较少的DNA传感器，是一种 潜在目标。我们假设，TRIM21通过预防系统性疾病而起到守门人的作用 由胞浆DNA感应驱动的不受控制的全身干扰素反应，如在UVB皮肤中显示的那样 这可能对系统性红斑狼疮的光敏性有影响。为了评估这一点，我们提出了以下建议： 目的1：评估TRIM21在UVB诱导的皮肤炎症中的作用及其对全身性炎症的影响 改变。我们将确定哪些免疫细胞是Trim21-/-小鼠全身性疾病的关键，以及如何刺痛- 而干扰素依赖和独立的通路介导了从局部到全身的转变 在没有TRIM21的情况下，对UVB的炎症反应。 目的2：确定TRIM21和DDX41在UVB反应中调节cGAS-STING信号的作用。 我们将调查TRIM21和DDX41是如何在UVB下游受到监管的，并询问它们的损失如何改变 结合生物化学和蛋白质组学研究刺痛信号体的组成、稳定性和功能。 目的3：明确TRIM21的缺失如何促进皮肤和全身UVB驱动的干扰素反应。 对SLE患者的PBMC和皮肤活检的分析将确定TRIM21可能对 系统性红斑狼疮的光敏性以及刺痛在驱动这些反应中的作用。 影响：该项目将确定TRIM21这一迄今未知的作用背后的机制 控制UVB驱动的全身干扰素反应，并询问改变的TRIM21调节通路是否可以 解释紫外线照射与系统性红斑狼疮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.