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Myoferlin is an essential component of late-stage vRNP trafficking vesicles for enveloped RNA viruses.

ABSTRACT: The Rab11a endosomal recycling pathway is exploited by important respiratory RNA viruses such as IAV and RSV, aiding viral egress from the apical surface of polarized epithelial cells. Late in infection, Rab11a-containing vesicles specifically transport viral ribonucleoprotein (vRNP) complexes towards the cell surface before packaging and budding. Rather than employing traditional Rab11a-positive recycling endosomes, virus-infected cells generate remodelled Rab11a-containing vesicles, as observed during IAV infection. Besides Rab11a, no other conserved host co-factors have been identified among these various vRNP trafficking vesicles. Here we discovered and confirmed myoferlin’s association with IAV vRNPs in the cytoplasm and colocalisation with Rab11a during late stages of infection. We also found that this role was conserved in late-stage vRNP trafficking of other viruses, including RSV and SeV. Myoferlin likely recruits the EHD family of proteins, which are involved in endosomal biogenesis, to these unique vRNP trafficking endosomes, highlighting myoferlin’s pivotal role in viral replication.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Influenza

SUBMITTER: David Courtney

LAB HEAD: David Courtney

PROVIDER: PXD052709 | Pride | 2025-09-25

REPOSITORIES: Pride

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			Action	DRS
	P1332_Flag_1.raw	Raw
	P1332_Flag_2.raw	Raw
	P1332_Flag_3.raw	Raw
	P1332_WT1.raw	Raw
	P1332_WT2.raw	Raw

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Quantitative Live Cell Imaging Reveals Differential Manipulation of Rab11A Transport Pathways by Influenza virus and RSV

Project description:Assembly of infectious influenza A viruses (IAV) is a complex process involving transport from the nucleus to the plasma membrane. Rab11A containing recycling endosomes have been identified as a platform for intracellular transport of viral RNA (vRNA). Using high spatiotemporal resolution light-sheet microscopy (~1.4 volumes/s, 330 nm isotropic spatial resolution), we quantify Rab11A and vRNA movement in live cells during IAV infection. Here we report that IAV infection decreases speed and increases arrest of Rab11A. Unexpectedly, infection with RSV alters Rab11A motion in a manner opposite to IAV, suggesting that Rab11A is a common host component that is differentially manipulated by respiratory RNA viruses. Using two-color imaging we demonstrate co-transport between Rab11A and IAV vRNA in infected cells and provide direct evidence that vRNA-associated Rab11A have altered transport. The mechanism of altered Rab11A movement is likely related to a decrease in dynein motors bound to Rab11A vesicles during IAV infection.

2020-01-14 | PXD016331 | Pride

Identifying cellular RNA-binding proteins during infection uncovers a role for MKRN2 in influenza mRNA trafficking.

Project description:Utilisation of RNA-binding proteins (RBPs) is an important aspect of post-transcriptional regulation of viral RNA. Viruses such as influenza A viruses (IAV) interact with RBPs to regulate processes including splicing, nuclear export and trafficking, while also encoding RBPs within their genomes, such as NP and NS1. But with almost 1000 RBPs encoded within the human genome it is still unclear what role, if any, many of these proteins play during viral replication. Using the RNA interactome capture (RIC) technique, we isolated RBPs from IAV infected cells to unravel the RBPome of mRNAs from IAV infected human cells. This led to the identification of one particular RBP, MKRN2, that associates with and positively regulates IAV mRNA. Through further validation, we determined that MKRN2 is involved in the nuclear-cytoplasmic trafficking of IAV mRNA likely through an association with the RNA export mediator GLE1. In the absence of MKRN2, IAV mRNAs accumulate in the nucleus of infected cells, which we suspect leads to their degradation by the nuclear RNA exosome complex. MKRN2, therefore, appears to be required for the efficient nuclear export of IAV mRNAs in human cells.

2024-04-16 | PXD048870 | Pride

Influenza A virus-induced production of PI4P at the endoplasmic reticulum involves ATG16L1 and promotes the egress of viral ribonucleoproteins

Project description:To further understand the molecular mechanisms by which RAB11A is hijacked in IAV-infected cells, we sought to identify viral-induced changes in RAB11A interactome. To this end, we used a TurboID-based proximity labelling approach, most suitable for the detection of weak or transient protein-protein interactions (Figure 2A). TurboID is a highly active biotin ligase that rapidly converts biotin into biotin–AMP, a reactive intermediate which covalently labels proximal proteins within a 10-30 nm radius(REF DOI : 10.1038/s41596-020-0399-0). The RAB11A protein was fused to TurboID and stably expressed in A549 cells by lentiviral transduction (Supplementary Figure 2A western blot). The resulting A549-TurboID-RAB11A cell population was infected with the WSN virus at a MOI of 5 PFU/cell - conditions in which all cells are positive for the viral nucleoprotein (NP) upon immunostaining at 8 hpi (Supplementary Figure 2B IF-NP), or mock-infected. At 8 hpi, biotin was added to the culture medium for 10 min before cell lysates were prepared, and biotinylated proteins were purified with streptavidin beads, as described in REF. A fraction of the total lysates and the biotinylated eluates were analysed by mass spectrometry based-proteomics. Four independent biological replicates were performed.

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