The role of Arl17 in healthy and influenza A virus infected cells

Abstract

Influenza A virus (IAV) is an important human pathogen that causes epidemic and pandemic events of flu. The study of the viral life cycle and its interactions with the infected host is crucial for the development of novel therapeutic strategies. IAV has an eight-part segmented RNA genome organized in viral ribonucleoprotein complexes (vRNP), which are replicated in the nucleus of the cell. De novo synthesized vRNPs need to leave the nucleus to reach the cytosol for viral assembly, budding and release. Several pathways have been implicated in nuclear export of vRNPs, including CRM1, apoptosis activation and extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling cascade. Mitochondria are crucial organelles for the maintenance of cellular homeostasis, since they are responsible for the regulation of metabolism, apoptosis, calcium homeostasis and innate immunity. Their functions are tightly regulated by dynamic changes in mitochondrial morphology. Given their importance, many viruses modulate mitochondria to promote cellular environments favoring their proliferation. IAV has been shown to fragment mitochondria to decrease the antiviral immune response. Our lab identified a candidate modulator of mitochondrial morphology and IAV infection: the host GTPase Arl17. Our work demonstrated that depletion of Arl17 leads to a reduction in viral titers and promotes mitochondrial fragmentation, regardless of infection. Interestingly, this phenotype was not accompanied by alterations in IFNβ1 expression and mitochondrial unfolded protein response activation (UPRmt). However, ATP levels were significantly reduced in the absence of Arl17. Additionally, we showed that Arl17 is required for regular vRNP nuclear export. In its absence, we observed a delay in vRNPs nuclear export that was CRM1- and ERK1/2-independent. Therefore, influence of Arl17 on the induction of apoptosis should be further investigated as its inhibition could explain vRNPs nuclear export delay and it could be the element that links mitochondria and vRNPs nuclear export.