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PINK1 Inhibits Multimeric Aggregation and Signaling of MAVS and MAVS-Dependent Lung Pathology

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Abstract
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 in vitro assay. In vivo 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, in vivo 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.
Author(s)
이세원Chang Min YoonCharles S Dela CruzHyeon Jun ShinLokesh SharmaMin-Jong KangSang-Hun Kim
Issued Date
2021
Type
Article
Keyword
MAVS aggregationPTEN‐induced kinase 1inflammasomesmitochondrial antiviral signaling proteinmitochondrial signaling
DOI
10.1165/rcmb.2020-0490OC
URI
https://oak.ulsan.ac.kr/handle/2021.oak/7151
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_proquest_miscellaneous_2489250028&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,PINK1%20Inhibits%20Multimeric%20Aggregation%20and%20Signaling%20of%20MAVS%20and%20MAVS-Dependent%20Lung%20Pathology&offset=0&pcAvailability=true
Publisher
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Location
미국
Language
영어
ISSN
1044-1549
Citation Volume
64
Citation Number
5
Citation Start Page
592
Citation End Page
603
Appears in Collections:
Medicine > Medicine
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