UNC93B1

Systemic lupus erythematosus (SLE) is an autoimmune disease, in which the immune system that normally protects the body from invading microbes turns against the body's own cells. Researchers studied four patients from two families who developed symptoms of SLE in the first years of life. As familial occurrence of SLE in young children is highly unusual, the team searched for a primary genetic cause and found a mutation in the UNC93B1 gene in all affected family members. Systemic lupus erythematosus (SLE) is an autoimmune disease, in which the immune system that normally protects the body from invading microbes, turns against the body´s own cells. This autoimmune attack can affect any organ and patients commonly develop skin rashes, joint inflammation, blood clots, kidney failure, heart disease, fatigue and psychiatric problems. Until to date, there is no cure for SLE and patients are treated with immunosuppressing drugs with considerable side effects. A group of researchers lead by Min Ae Lee-Kirsch from the Department of Pediatrics, Medical Faculty, TUD Dresden University of Technology (Germany), studied four patients from two families who developed symptoms of SLE in the first years of life. As familial occurrence of SLE in young children is highly unusual, her team searched for a primary genetic cause and found a mutation in the UNC93B1 gene in all affected family members. UNC93B1 is a membrane-spanning structural protein required for maturation and trafficking of a group of receptors that play an important role in the defense against viral infections. These receptors recognize the nucleic acid component of the virus and activate type I interferons, which instruct cells to fight a viral infection. However, nucleic acids, such as DNA and RNA, are not only found in viruses, but are also present in every cell of the human body. This means that the immune system must be capable of discriminating foreign from self nucleic acids. The identified UNC93B1 mutations lead to selective overactivation of TLR7, one of the UNC93B1-regulated receptors that specifically recognizes RNA, leading to erroneous recognition of self RNA with uncontrolled overproduction of type I interferon. This results in an immune attack on normal cells which then triggers inflammation. Moreover, this also stimulates the survival of self-reactive B cells that produce autoantibodies directed against the body´s own cells, fueling the autoimmune attack. These findings demonstrate that UNC93B1 controls the activity of specific nucleic acid receptors, such as TLR7, thereby preventing autoimmunity. Remarkably, people lacking functional UNC93B1 are prone to viral infections with a severe course, such as herpes simplex virus encephalitis and severe COVID-19, highlighting the essential role of UNC93B1 for a healthy immune system. The findings of this study are also of clinical relevance regarding the development of novel targeted therapies for patients with common forms of SLE, who often show signs of overactivation of the TLR7 pathway. Professor Lee-Kirsch says: "Our study demonstrates a direct causal link between an overactive UNC93B1/TLR7 axis and lupus pathogenesis and indicates that blocking overactive TLR7 might be therapeutically effective. As such, our findings are expected to accelerate further development of TLR7 inhibitors for patients with SLE and related autoimmune diseases." The study was funded in part by the German Research Foundation (Deutsche Forschungsgemeinschaft; DFG) and the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung; BMBF). Results were published in Science Immunology as early release on January 11, 2024.

cGAS–STING通路是一种进化上保守的免疫信号通路，对微生物防御至关重要（STING：天然免疫新核心，免疫治疗新靶点）。与其他主要依赖于固定信号事件的先天免疫途径不同，STING在细胞中具有高度的流动性，流动性异常与神经退行性疾病等相关。STINGSTING是一种跨膜蛋白，以二聚体的形式存在于内质网上，其CDN结合结构域面对细胞质。在配体结合之前，每个STING单体的连接区域被交叉，配体结合结构域位于各自的跨膜结构域的另一侧。cGAMP的结合诱导了连接体区域的结构重排，其中配体结合结构域被旋转到与跨膜结构域平行。这种旋转被认为是STING激活和内质网通过COPII囊泡离开的关键。然后STING易位到内质网中间室（ERGIC）和高尔基体，在那里它招募激酶TBK1，它磷酸化STING本身和转录因子IRF3。磷酸化的IRF3易位到细胞核，启动IFN-I基因和ISGs的转录。此外，在这一过程中，STING激活了其他IFN非依赖的信号通路，分子细节未知。STING囊泡然后退出反式高尔基网络（TGN），继续前往核内体和溶酶体，在那里，STING囊泡最终被降解以终止信号传导。STING转运三步1. STING在内质网上STING不包含将其引导到内质网的信号序列，但为什么STING定位于内质网，并保持在内质网?帮助内质网保持STING的过程包括Ca2+传感器基质相互作用分子1（STIM1）和逆行COPII囊泡运输。STIM1通过钙通道控制Ca2+进入内质网，这在淋巴细胞的激活和增殖中至关重要。STIM1也通过直接绑定STING的ER保留因子。使用2,3-cGAMP的刺激会破坏这种相互作用，从而允许STING内质网退出。STIM1的缺失从内质网释放出STING，导致tonic IFN-I信号。所以STIM1缺陷的患者同时出现淋巴细胞减少（由于淋巴细胞中的钙通量缺陷）和自身免疫病。高尔基体-内质网逆行穿梭也起着重要作用。STING不是简单地固定在静息状态下的内质网上；相反，它通过分泌途径不断移动。内质网保留因素和逆行穿梭的结合可能建立了STING内质网定位的“表象”。此外，还有其他的辅助因子负责调节内质网上的STING蛋白水平，包括toll相互作用蛋白（TOLLIP）、E3泛素连接酶三部分基序蛋白30α（TRIM30α）和PTPN1/ 2，它们分别调节稳态下STING的溶酶体和蛋白酶体降解。2. 从内质网转移至高尔基体配体结合后，STING开始从内质网易位到高尔基体，这个过程需要COPII囊泡的组装。Sar1、Sec13、和Sec31的丢失阻止了STING配体结合时离开内质网，并减弱了STING信号。除了经典的COPII囊泡装置外，内质网上的其他一些蛋白质和复合物对STING从内质网到高尔基体的运输也很重要。在没有转位子复合物成分TRAPβ的情况下，配体诱导的STING运输被阻止。内质网蛋白iRhom2促进TRAPβ和STING的相互作用。与TRAPβ缺陷类似，iRhom2的丢失也会阻止STING从ER离开。由于TRAPβ和iRhom2不影响COPII装置的蛋白质运输，它们可能调节内质网的横向移动，以到达ER出口位点。一旦STING到达高尔基体，就会引发一系列的生化事件：(1)通过CTT招募TBK1；(2) TBK1磷酸化STING（丝氨酸366）和自身；(3)STING使IRF3聚合并招募到ILxIS基序，TBK1磷酸化IRF3；(4) p-IRF3二聚并易位到细胞核以开启免疫基因表达。除了磷酸化，其他翻译后修饰对高尔基体上的刺信号至关重要。例如，STING在半胱氨酸88和91处被顺式高尔基体定位的酰基转移酶DHC3/7/15棕榈酰化。用硝基呋喃衍生物C-178、C-179和H-151阻断刺棕榈酰化，可以防止STING寡聚和信号体组装。多种蛋白（AMFR、INSIG1、ZDHHC1、RNF26、TRIM32和TRIM56）对STING的泛素化对高尔基体的信号转导也很重要。此外，一些蛋白质辅助因子直接或间接地促进高尔基体上刺信号体的形成。S6K和SREBP裂解激活蛋白（SCAP）促进IRF3招募到STING-TBK1。而核心自噬蛋白ATG9a在膜扩张中负调控STING-TBK1复合物的形式和下游IFN信号传导，蛋白磷酸酶Mg2+/Mn2+依赖的1a和蛋白磷酸酶6催化亚基通过去磷酸化抑制信号传导。IFN-高尔基体易位也是抑制独立活性所必需的。例如，STING介导的NF-κB信号通路需要TBK1与高尔基体上的刺c端结合，但不需要STING磷酸化。STING介导的自噬需要STING从内质网转移到ER-GIC，这是自噬膜的一个已知来源。STING介导的UPR和细胞死亡需要STING从内质网退出。有趣的是，STING介导的UPR和自噬活性都被定位到相同的基序上（一个包含氨基酸322-343的α-螺旋），这表明这两种活性可能依赖于一个尚未确定的共同过程。STING内质网单独退出（在到达ERGIC或高尔基体之前）是否诱导任何细胞信号也不清楚。3. 后高尔基体穿梭和溶酶体降解虽然有许多已知的STING辅助因子在内质网到高尔基体阶段起作用，但已知的高尔基体后STING转运的辅助因子要少得多。后高尔基体的STING运输减弱了IFN信号。因此，这些辅助因子的功能缺失将延长STING信号。一旦STING在高尔基体上被磷酸化，STING降解的过程就开始了。适配器蛋白复合物1（AP-1）结合一个双亮氨酸基序以及在STING CTT结构域磷酸化的S366残基。然后，AP-1将磷酸化的STING分类到clathrin蛋白包被的囊泡中，运输到内溶酶体。AP-1的抑制增强了STING信号。STING高尔基体出口也需要反式高尔基GRIP和包含蛋白2的螺旋-螺旋结构域2（GCC2/ GCC185）。GCC2属于TGN上的Golgin蛋白家族，通过APs将囊泡转移到RAB GTPases。TGN是一个主要的分拣枢纽，在这里各类物质被分类到各种运输工具，以贩运到细胞的不同区室)。一旦STING到达核内体，它再次被UBE2N泛素化。HGS、VPS37A、UBAP1、Tsg101和Vps4是STING辅助因子。C9ORF72和UNC93B1也能促进STING溶酶体降解，尽管分子细节仍有待确定。STING还驱动非经典的自噬，这可能有助于其自身被自噬小体降解。目前还不清楚STING囊泡是与溶酶体融合还是被溶酶体吞噬，以及膜拓扑结构在每种情况下是如何工作的。参考资料Chu, T.-T., X. Tu, K. Yang, J. Wu, J.J. Repa, and N. Yan. 2021. Tonic primeboost of STING signalling mediates Niemann-Pick disease type C. Nature. 596:570–57Decout, A., J.D. Katz, S. Venkatraman, and A. Ablasser. 2021. The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat. Rev. Immunol. 21:548–569