Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles

Ming Yuan Li, Trupti Shivaprasad Naik, Lewis Yu Lam Siu, Oreste Acuto, Eric Spooner, Peigang Wang, Xiaohan Yang, Yongping Lin, Roberto Bruzzone, Joseph Ashour, Matthew J Evans and Sumana Sanyal ()
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Ming Yuan Li: HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Trupti Shivaprasad Naik: HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Lewis Yu Lam Siu: HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Oreste Acuto: Sir William Dunn School of Pathology, University of Oxford
Eric Spooner: Nine Cambridge Center
Peigang Wang: School of Basic Medical Sciences, Capital Medical University
Xiaohan Yang: Medical Genetic Centre, Guangdong Women and Children Hospital
Yongping Lin: The First Affiliated Hospital of Guangzhou Medical University
Roberto Bruzzone: HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong
Joseph Ashour: Department of Microbiology, Icahn School of Medicine at Mount Sinai
Matthew J Evans: Department of Microbiology, Icahn School of Medicine at Mount Sinai
Sumana Sanyal: HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Among the various host cellular processes that are hijacked by flaviviruses, few mechanisms have been described with regard to viral egress. Here we investigate how flaviviruses exploit Src family kinases (SFKs) for exit from infected cells. We identify Lyn as a critical component for secretion of Dengue and Zika infectious particles and their corresponding virus like particles (VLPs). Pharmacological inhibition or genetic depletion of the SFKs, Lyn in particular, block virus secretion. Lyn−/− cells are impaired in virus release and are rescued when reconstituted with wild-type Lyn, but not a kinase- or palmitoylation-deficient Lyn mutant. We establish that virus particles are secreted in two distinct populations – one as free virions and the other enclosed within membranes. Lyn is critical for the latter, which consists of proteolytically processed, infectious virus progenies within autophagosome-derived vesicles. This process depends on Ulk1, Rab GTPases and SNARE complexes implicated in secretory but not degradative autophagy and occur with significantly faster kinetics than the conventional secretory pathway. Our study reveals a previously undiscovered Lyn-dependent exit route of flaviviruses in LC3+ secretory organelles that enables them to evade circulating antibodies and might affect tissue tropism.

Date: 2020
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DOI: 10.1038/s41467-020-19028-w

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