Capsaicin functions as a selective degrader of STAT3 to enhance host resistance to viral infection
Capsaicin functions as a selective degrader of STAT3 to enhance host resistance to viral infection
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DOI：
10.1038/s41401-023-01111-9
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发表时间：
2023-06-13
影响因子：
8.2
通讯作者：
Xu，An-long
中科院分区：
文献类型：
--
作者：
Zhang，Mei-qi;Jia，Xin;Xu，An-long
尽管 STAT3 已被报道为 I 型干扰素 (IFN) 信号传导的负调节因子，但药理抑制 STAT3 对先天抗病毒免疫的影响尚不清楚。辣椒素被批准用于治疗带状疱疹后神经痛和糖尿病周围神经痛，是一种瞬时受体电位香草酸亚型 1 (TRPV1) 的激动剂，在抗癌、抗炎和代谢疾病方面具有公认的功效。我们研究了辣椒素对病毒复制和先天抗病毒免疫反应的影响，发现辣椒素剂量依赖性地抑制 VSV、EMCV 和 H1N1 的复制。在感染 VSV 的小鼠中，用辣椒素预处理可提高存活率并抑制炎症反应，同时减弱肝脏、肺和脾中的 VSV 复制。辣椒素对病毒复制的抑制与 TRPV1 无关，并且主要发生在病毒进入后步骤。我们进一步发现辣椒素直接与STAT3蛋白结合并选择性促进其溶酶体降解。结果，STAT3对I型IFN反应的负调节减弱，宿主对病毒感染的抵抗力增强。我们的结果表明辣椒素是一种有前途的小分子候选药物，并为增强宿主对病毒感染的抵抗力提供了可行的药理学策略。
Although STAT3 has been reported as a negative regulator of type I interferon (IFN) signaling, the effects of pharmacologically inhibiting STAT3 on innate antiviral immunity are not well known. Capsaicin, approved for the treatment of postherpetic neuralgia and diabetic peripheral nerve pain, is an agonist of transient receptor potential vanilloid subtype 1 (TRPV1), with additional recognized potencies in anticancer, anti-inflammatory, and metabolic diseases. We investigated the effects of capsaicin on viral replication and innate antiviral immune response and discovered that capsaicin dose-dependently inhibited the replication of VSV, EMCV, and H1N1. In VSV-infected mice, pretreatment with capsaicin improved the survival rate and suppressed inflammatory responses accompanied by attenuated VSV replication in the liver, lung, and spleen. The inhibition of viral replication by capsaicin was independent of TRPV1 and occurred mainly at postviral entry steps. We further revealed that capsaicin directly bound to STAT3 protein and selectively promoted its lysosomal degradation. As a result, the negative regulation of STAT3 on the type I IFN response was attenuated, and host resistance to viral infection was enhanced. Our results suggest that capsaicin is a promising small-molecule drug candidate, and offer a feasible pharmacological strategy for strengthening host resistance to viral infection.