Kim Sang-Hun, Shin Hyeon Jun, Yoon Chang Min, Lee Sei Won, Sharma Lokesh, Dela Cruz Charles S, Kang Min-Jong
Department of Internal Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, Connecticut; and.
Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Am J Respir Cell Mol Biol. 2021 May;64(5):592-603. doi: 10.1165/rcmb.2020-0490OC.
Mitochondria have emerged as important signaling organelles where intracellular perturbations are integrated and, consequently, intracellular signaling pathways are modulated to execute appropriate cellular functions. MAVS (mitochondrial antiviral signaling protein) represents such an example that functions as a platform molecule to mediate mitochondrial innate immune signaling. Recently, multimeric aggregation of MAVS has been identified as a key molecular process for its signaling. The underlying mechanisms to regulate this, however, are still incompletely understood. We hypothesized that PINK1 (PTEN-induced kinase 1) plays an important role in the regulation of multimeric MAVS aggregation and its consequent pathobiology. To test whether PINK1 interacts with MAVS, bimolecular fluorescence complementation analysis and IP were performed. RLH (RIG-I-like helicase) and NLRP3 inflammasome signaling were evaluated by assay. functional significance of PINK1 in the regulation of MAVS signaling was evaluated from both murine modeling of influenza viral infection and bleomycin-induced experimental pulmonary fibrosis, wherein MAVS plays important roles. Multimeric MAVS aggregation was induced by mitochondria dysfunction, and, during this event, the stabilized PINK1 interacted physically with MAVS and antagonized multimeric MAVS aggregation. Accordingly, the MAVS-mediated antiviral innate immune and NLRP3 inflammasome signaling were enhanced in PINK1 deficiency. In addition, studies revealed that MAVS-mediated pulmonary antiviral innate immune responses and fibrotic responses after bleomycin injury were enhanced in PINK1 deficiency. In conclusion, these results establish a new role of PINK1 in the regulation of MAVS signaling and the consequent pulmonary pathobiology.
线粒体已成为重要的信号细胞器，在其中整合细胞内扰动，进而调节细胞内信号通路以执行适当的细胞功能。MAVS（线粒体抗病毒信号蛋白）就是这样一个例子，它作为一个平台分子介导线粒体先天免疫信号传导。最近，MAVS的多聚体聚集已被确定为其信号传导的关键分子过程。然而，调节这一过程的潜在机制仍未完全清楚。我们假设PINK1（PTEN诱导激酶1）在调节多聚体MAVS聚集及其后续病理生物学过程中起重要作用。为了测试PINK1是否与MAVS相互作用，进行了双分子荧光互补分析和免疫沉淀。通过检测评估RLH（RIG-I样解旋酶）和NLRP3炎性小体信号传导。从流感病毒感染的小鼠模型和博来霉素诱导的实验性肺纤维化中评估PINK1在调节MAVS信号传导中的功能意义，其中MAVS起重要作用。线粒体功能障碍诱导多聚体MAVS聚集，在此过程中，稳定的PINK1与MAVS发生物理相互作用并拮抗多聚体MAVS聚集。因此，在PINK1缺乏时，MAVS介导的抗病毒先天免疫和NLRP3炎性小体信号传导增强。此外，研究表明，在PINK1缺乏时，博来霉素损伤后MAVS介导的肺部抗病毒先天免疫反应和纤维化反应增强。总之，这些结果确立了PINK1在调节MAVS信号传导及后续肺部病理生物学过程中的新作用。
