RT Journal Article
SR Electronic
T1 Activation of Src-family kinases orchestrate secretion of flaviviruses by targeting mature progeny virions to secretory autophagosomes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.12.903062
DO 10.1101/2020.01.12.903062
A1 Ming Yuan Li
A1 Trupti Shivaprasad Naik
A1 Lewis Yu Lam Siu
A1 Oreste Acuto
A1 Eric Spooner
A1 Peigang Wang
A1 Xiaohan Yang
A1 Yongping Lin
A1 Roberto Bruzzone
A1 Joseph Ashour
A1 Sumana Sanyal
YR 2020
UL http://biorxiv.org/content/early/2020/01/14/2020.01.12.903062.abstract
AB Among the various host cellular processes that are hijacked by flaviviruses, very few mechanisms have been described with regard to viral secretion. Here we investigated how flaviviruses exploit the Src family kinases (SFKs) for exit from infected cells. We isolated three members of the SFK family – Src, Fyn and Lyn – that were specifically activated during secretion of Dengue and Zika or their corresponding virus like particles (VLPs). Pharmacological inhibition or genetic depletion of the SFKs blocked virus secretion, most significantly upon Lyn-deficiency. Lyn-/- cells were severely impaired in virus release, and were rescued when reconstituted with wild-type Lyn, but not a kinase- or palmitoylation-deficient Lyn mutant. We further established that Lyn, via its palmitoylation-dependent membrane association, triggered post-Golgi virus transport in specialised Rab11 and Transferrin receptor positive organelles resembling secretory autophagosomes, and distinct from conventional exocytic vesicles. In the absence of Lyn activity or its aberrant membrane association, virions were sorted into the lysosomal pathway for degradation. This mode of export was specifically triggered by processed, and mature, but not by furin-resistant virus particles, and occurred with significantly faster kinetics than the conventional secretory pathway. Our study therefore charts a previously undiscovered Lyn-dependent exit strategy, triggered by flaviviruses in secretory autophagosomes that might enable them to evade circulating antibodies and dictate tissue tropism.