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Mohamud, Yasir

University of British Columbia

Coxsackievirus B3 (CVB3) is a positive single-strand RNA virus of the enterovirus genus that is implicated in diverse human pathologies from viral myocarditis to neurological disorders. CVB3 infection has been linked to the cellular activation of the host autophagy pathway but the underlying mechanisms remain unclear. The central hypothesis of the current dissertation is that that CVB3 usurps the host autophagy pathway to promote viral propagation. To address this hypothesis, I proposed to investigate how CVB3 disrupts important steps in the autophagy pathway including the initiation of autophagosome biogenesis, selective recruitment of cargo, fusion of autophagosomes with lysosomes, and overall lysosomal function. I have demonstrated that CVB3 infection disrupts multiple stages of the autophagy pathway to favor viral pathogenesis, including the initiation of autophagosome biogenesis, the selective recruitment of substrates, the fusion of autophagosomes with lysosomes, as well as lysosomal function. In particular, I uncovered that CVB3 targets autophagy initiation factors such as ULK1/2, through viral proteinase-mediated cleavage, to disrupt canonical autophagy signaling that is activated following physiological stimuli such as starvation. Instead, I showed that CVB3 utilizes viral proteins to initiate non-canonical autophagy that relies on PI4PKIIIβ kinase. In addition to disrupted autophagosome biogenesis, I reported that CVB3 also targets the selective autophagy process by cleaving autophagy adaptor proteins NDP52/CALCOCO2 through the activity of viral proteinase 3C, consistent with our previous reports on adaptor proteins SQSTM1/p62 and NBR1. Furthermore, I uncovered that CVB3 impairs the clearance function of autophagy by disrupting the autophagosome-lysosome fusion process, in part through the cleavage of fusion adaptor and tethering factors SNAP29 and PLEKHM1, respectively. Lastly, I identified that CVB3 targets the master regulator of lysosomal biology, TFEB, through viral proteinase 3C-mediated cleavage to disrupt lysosome function. Collectively, I identify viral proteinases as important pathogenic factors that not only facilitate viral maturation but also disrupt the cellular recycling machinery of autophagy at multiple stages. These findings are significant because they provide a strong foundation for targeting autophagy as a strategy to combat viral pathogenesis.

Text

2021-06-17

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/78727

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/