Hepatitis A virus structural protein pX interacts with ALIX and promotes the secretion of virions and foreign proteins through exosome‐like vesicles

Abstract

Hepatitis A virus (HAV), a classic nonenveloped virus, has recently been found to be released mainly in the form of quasi-enveloped HAV (eHAV) by hijacking host endosomal sorting complexes required for transport (ESCRT) complexes. Unlike the nonenveloped virion, eHAV contains the viral protein pX on the surface of the HAV capsid as an extension of VP1. How HAV capsids acquire the host envelope and whether the pX protein is involved in this process were previously unknown. Here, we analyse the role of pX in foreign protein secretion in exosome-like extracellular vesicles (EVs) and the formation of eHAV. Fusion of pX to eGFP guided eGFP into exosome-like EVs through directing eGFP into multivesicular bodies (MVBs), and apoptosis-linked gene 2-interacting protein X (ALIX) release was significantly enhanced. Coimmunoprecipitation (co-IP) demonstrated the interaction between pX and the ALIX V domain. Removal of the C-terminal half of pX abolished eHAV release and reduced the interaction between the HAV virion and ALIX. Finally, the C-terminal half of pX alone was sufficient for loading eGFP into EVs by interacting with ALIX. In conclusion, the C-terminal part of pX is important for eHAV production and may have potential for large protein complex loading into exosome-like EVs for therapeutic purposes.

A non-enveloped arbovirus released in lysosome-derived extracellular vesicles induces super-infection exclusion

“…It has been reported that Hepatitis A virus and hepatitis E virus exit cells inside exosomes derived from the MVBs [ 3 , 5 , 24 ], that are characterised by the presence of endosomal compartments and vesicular transport markers, such as Flotillin 2, CD63 or members of the ESCRT protein family. These exosomes are around 50-200nm in size [ 25 ].…”

Exosomal miRNAs in tumor microenvironment

“…A large amount of literature has reported that tumor-derived exosomal miRNAs can reshape TME and promote tumor progression, but little is known about the sorting mechanism of exosomal miRNAs. Although the basic framework of the endosome sorting complex required for transport (ESCRT) and Ago2 in MVB sorting has been reported in previous studies, it remains to be elucidate whether other novel sorting signals are involved in the release of exosomal miRNAs [86,[181][182][183][184].…”

Exosome: A New Player in Translational Nanomedicine

“…External factors, such as the impact of viral infection on exosome production through mechanisms including the regulation of specific proteins, are closely associated with exosome biogenesis [61][62][63]. The hepatitis A virus (HAV) can hijack ALIX exosome-like pathways [64,65], while the respiratory syncytial virus (RSV) uses the exosome cargo to inhibit immune responses in the course of viral infection [66]. Bacterial and parasitic infections also affect exosome production and secretion [67,68], while metabolic dysfunction due to abiotic stress can also lead to exosomal changes.…”