APOBEC3G

IL-27是IL-6家族的成员，在结构上与 IL-12 和 IL-6家族相关。其受体IL-27R通过JAK/STAT信号通路传导。IL-6家族6个促癌成员IL-27R由IL-27Rα和gp130链构成，其中gp130还是IL-35、IL-6、IL-11等细胞因子受体的重要组成部分。此外，gp130和IL-27Rα可以在包括NIH3T3细胞、B细胞、T细胞、NK细胞、DC、单核细胞、肥大细胞、内皮细胞和脂肪细胞等细胞中表达。健康人体中，IL-27可由DC、巨噬细胞和单核细胞等APC通过TLR和IFN-γ依赖的方式产生。IL-27在肿瘤、自免和肥胖炎症作用中均表现出多效性。抗肿瘤已报道的作用机制包括：抑制肿瘤作用促进肿瘤作用诱导产生IFN-γ，提高肿瘤特异性CD8+ T细胞的存活率和分化能力激活NFIL3和T-bet来诱导TIM-3表达激活T细胞和NK细胞介导的肿瘤免疫反应激活STAT1，驱动Treg表达CD39，从而发挥Treg促瘤作用促进造血干细胞扩增和分化为M1表型髓系祖细胞激活STAT1，介导PD-L1表达介导CD8+ T细胞免疫反应诱导癌变B细胞凋亡激活NK细胞，通过Fas/FasL依赖诱导肿瘤细胞凋亡与多肌胞嘧啶结合，通过增强TLR3表达诱导肿瘤细胞凋亡通过诱导产生CXCL10和IFN-γ诱导的单核因子，抑制肿瘤组织新生血管形成。通过下调促血管生成相关基因(如VEGFR1、PTGS1、COx-1和FGFR3)和上调抗血管生成相关基因(如IP-10和TIP3)，阻碍肿瘤新血管生成。IL-27被用来预测乳腺癌生存、免疫检查点表达、免疫细胞浸润。联合PD-1/PD-L1、IDO阻断剂可能是更好的策略。J Immunother Cancer. 2023;11(11):e007530. 抑肥胖理论上，IL-27/IL-27Rα信号能够抵御肥胖和胰岛素抵抗的发展，促进产热和能量消耗。但实际上，IL-27在调节脂肪细胞内炎症反应方面具有双重作用。在体外细胞实验中检测到，在TNF-α或LPS刺激下，前脂肪细胞和脂肪细胞均可分泌IL-27。Acta Physiologica Sinica已知机制包括：抑制肥胖发展促进肥胖发展通过WSX-1信号特异性调控小鼠内脏脂肪组织内Treg数量，进而抑制肥胖的发展。在没有炎症因子干预的情况下，IL-27 刺 激 前 脂 肪 细 胞 后， 可 通 过 激 活ERK和JNK/STAT3途径降低MCP-1、IL-6、TNF-α和COX-2经典炎症基因mRNA的表达，抑制炎症反应。当肥胖已诱发炎症时，IL-27会加重脂肪组织内炎症的进展。在HFD喂养的 IL-27Rα敲除小鼠模型中，脂肪组织中IL-6、TNF-α增加，巨噬细胞浸润增加。直接作用于脂肪细胞，通过p38MAPK/PGC-1α 信号通路诱导产热效应子 UCP1 的表达，促进产热，进而调节肥胖。在体外细胞实验中检测到，在 TNF-α或LPS刺激下，前脂肪细胞和脂肪细胞均可分泌 IL-27。体外实验中，在培养基中加入TNF-α后，IL-27能与TNF-α协同作用，显著增加MCP-1、IL-6、COX-2和TNF-α的表达。同时，成人和儿童的IL-27作用也有差异。有研究显示，成人血清IL-27水平会随着肥胖程度的加重而降低，且在减肥成功后 IL-27 的水平恢复正常。但肥胖儿童血浆中则观察到IL-27水平升高。抗自免以类风湿关节炎(RA)为例：抑制促炎因子分泌致病作用在RA发病早期，IL-27可能通过抑制IL-17和IL-6的分泌，延缓RA的进程。可通过诱导FLS表达粘附分子及释放炎症趋化因子加重RA。可通过与IL-6竞争二者共同的受体亚基gp130而自然拮抗IL-6激活mTOR信号通路，导致外周血中B细胞的失调及功能异常。在RA滑膜中， IL-27能抑制TNF-α或者IL-17A刺激下的FLS产生IL-6。能抑制初始CD4+ T细胞分化为Th17细胞，并通过STAT1依赖性途径抑制Th17细胞的发育，进而减少IL-17的产生。抑制TNF-α诱导产生CCL20，间接阻碍包括Th17细胞在内的CCR6+细胞群的募集，从而减少IL-17分泌。肠道驻留的Treg细胞还会在肠道炎症期间产生IL-27，以限制潜在Th17的分化，从而抑制对肠道细菌的促炎作用，并减轻了自身免疫和自体炎症条件下的肠道损伤。值得注意的是，IL-27和IL-10由不同的Treg细胞组产生。IL-27作为Treg细胞来源的肠道Th17反应抑制因子的具体机制尚不明确，可能是通过STAT1和STAT3受体发出信号。Nat Immunol抗病毒IL-27 可以在PBMC、CD4+ T细胞、MDM及DC等不同免疫细胞中阻碍HIV病毒的复制，其作用机制可能包括：通过激活 CD4+ T细胞中的抗病毒蛋白基因；调节Th1/Th2比率；诱导MDM中 IFIG表达；上调巨噬细胞中的免疫限制因子APOBEC3G及BST-2；下调宿主因子 SPTBN1 及抑制 YB-1 的乙酰化发挥其抑制作用，等等。小结目前进展最快的IL-27单抗应该是Surface的SRF388Coherus的casdozokitug，均已进入2期临床。2024年1月，Coherus在公布了casdozokitug联合疗法治疗局部晚期或转移性肝细胞癌的2期数据，ORR为38%(n=29)，其中3例患者实现完全缓解。本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处·····

来自冲绳科学技术大学院大学等机构的科学家们通过研究利用冷冻电子显微镜技术揭示了APOBEC3G-Vif复合体的原子结构。 如今，科学家们一直致力于揭开HIV中A3G-Vif相互作用的基础，其二者之间的相互作用是HIV逃避机体抗病毒先天性免疫反应的关键机制。HIV-1能通过与其它病毒感染因子（Vif，viral infectivity factor）的结合来中和宿主机体的细胞防御。 近日，一篇发表在国际杂志Nature Communications上题为“Structural insights into RNA bridging between HIV-1 Vif and antiviral factor APOBEC3G”的研究报告中，来自冲绳科学技术大学院大学等机构的科学家们通过研究利用冷冻电子显微镜技术揭示了APOBEC3G-Vif复合体的原子结构。 研究者Matthias Wolf说道，APOBEC3G (A3G)是人类先天性免疫系统用来抵御入侵病毒的关键组分，其就好像特洛伊木马一样能进入出芽的病毒颗粒中，这样其就能在所感染的细胞中病毒进行逆转录后修饰并失活病毒的DNA。然而HIV-1已经进化出了一种以Vif蛋白形式存在的抵抗机制，其能通过与A3G结合并对其进行降解来抑制这一过程的发生，从而成功扩增感染性的病毒颗粒。 科学家揭示免疫逃逸HIV蛋白复合体的特殊结构。 图片来源：Nature Communications (2023). DOI:10.1038/s41467-023-39796-5 这项研究的一个独特之处在于，其首次揭示了这种复合体的形成或许是由特定的RNA序列所介导的，尽管单链DNA是A3G的降解底物，其蛋白结构能被优化为具有更高的溶解度，并且能在体外复制A3G泛素化的降解途径，A3G泛素化是一种能将泛素多泛素化转移到靶向蛋白的过程，其在多种生理学功能中都非常重要。 这项研究中，研究人员确定了蛋白质和RNA配体之间的特定相互作用，这或许就能作为未来抑制A3G-Vif仙湖作用的HIV/AIDS抗病毒疗法治疗的靶标。最后研究者表示，对A3G, Vif, 和RNA配体之间相互作用的进一步评估表明，A3G-Vif的组装和随后的泛素化能通过界面上的氨基酸突变或多核苷酸修饰来进行控制，这就表明，特定的化学片段或许就是抑制A3G-Vif之间相互作用最有希望的药效团（pharmacophore）。（生物谷Bioon.com） 原始出处： Kouno, T., Shibata, S., Shigematsu, M. et al. Structural insights into RNA bridging between HIV-1 Vif and antiviral factor APOBEC3G. Nat Commun 14, 4037 (2023). doi：10.1038/s41467-023-39796-5

Cancer therapies that target specific genetic abnormalities in tumors have revolutionized treatment possibilities over the past two decades. While quality of life and survival are improved with targeted therapies, relapse is common due to the evolution of new tumor cells that are resistant to the targeted therapy. A new study reveals how lung tumors may develop drug resistance over time, pointing to a protein, called APOBEC3A, that could be a promising target. Results may help researchers develop new solutions for tumor resistance to targeted cancer therapies. Cancer therapies that target specific genetic abnormalities in tumors have revolutionized treatment possibilities over the past two decades. While quality of life and survival are improved with targeted therapies, relapse is common due to the evolution of new tumor cells that are resistant to the targeted therapy. A new study by investigators from the Mass General Cancer Center, a member of the Mass General Brigham healthcare system, reveals how lung tumors may develop drug resistance over time, pointing to a protein, called APOBEC3A, that could be a promising target. Results, published in Nature, may help researchers develop new solutions for tumor resistance to targeted cancer therapies. "Traditionally, we treat patients with a drug until the tumor progresses and then we look at what happened in the tumor and try to decide on the next therapy based on what we see in the tumor," said corresponding author Aaron Hata, MD, PhD, of the Mass General Cancer Center. "In that sense, the tumor is always one step ahead and we need to react to it. By understanding the fundamental mechanisms of tumor evolution, we can get ahead of the tumor, understand what's driving it, and be able to intervene earlier." In this study, the authors analyzed non-small-cell lung cancer (NSCLC) tumor cells treated with tyrosine kinase inhibitors (TKIs), a type of targeted therapy. The researchers performed genetic analysis on patient tumors as well as experimentally derived TKI-resistant cells, finding that in both settings, the small population of tumor cells that survived after TKI treatment accumulated mutations of the APOBEC mutation signature. The authors found that the tumor cells surviving TKI treatment overexpress a type of APOBEC protein, APOBEC3A, which appears to cause drug resistance in two main ways. APOBEC3A can directly cause mutations that are known to result in tumor resistance, such as mutations in the ALK gene. In other cases, the cause of drug resistance is less direct, though the researchers hypothesize that APOBEC3A causes extensive DNA damage that helps push tumor cells into a "persister" state that is more resistant to treatment. The researchers demonstrated that cell lines without the APOBEC3A gene did not become resistant to targeted therapies as fast as those with the gene. This suggests that targeting APOBEC could extend patients' response to existing targeted therapies; however, no drug exists yet to target APOBEC. Going forward, the researchers hope to gain further insight into the mechanisms by which APOBEC causes drug resistance, which may shed more light on how to develop a drug to inhibit APOBEC expression or activity. While many NSCLC patients with targeted therapy-resistant tumors have APOBEC mutations, the patients that do not have these mutations would require other solutions. Furthermore, it is not yet clear whether APOBEC drives acquired drug resistance in other cancer types or with use of other targeted therapies. "Many new cancer therapies that have been developed in the genomic era specifically target 'driver mutations,' such that they do not hurt healthy cells and only affect cells with the mutation driving the tumor progression," said corresponding author Michael Lawrence, PhD, of the Mass General Cancer Center. "Very often, however, a tumor will return, having undergone a change that allows it to survive in the presence of the drug. Our research helps us understand the mechanisms that drive the process of drug resistance, which begin before the tumor becomes resistant."