Lassa virus Z protein hijacks the autophagy machinery for efficient transportation by interrupting CCT2-mediated cytoskeleton network formation

ABSTRACT

The Lassa virus (LASV) is a widely recognized virulent pathogen that frequently results in lethal viral hemorrhagic fever (VHF). Earlier research has indicated that macroautophagy/autophagy plays a role in LASV replication, but, the precise mechanism is unknown. In this present study, we show that LASV matrix protein (LASV-Z) is essential for blocking intracellular autophagic flux. LASV-Z hinders actin and tubulin folding by interacting with CCT2, a component of the chaperonin-containing T-complexes (TRiC). When the cytoskeleton is disrupted, lysosomal enzyme transit is hampered. In addition, cytoskeleton disruption inhibits the merge of autophagosomes with lysosomes, resulting in autophagosome accumulation that promotes the budding of LASV virus-like particles (VLPs). Inhibition of LASV-Z-induced autophagosome accumulation blocks the LASV VLP budding process. Furthermore, it is found that glutamine at position 29 and tyrosine at position 48 on LASV-Z are important in interacting with CCT2. When these two sites are mutated, LASV-mut interacts with CCT2 less efficiently and can no longer inhibit the autophagic flux. These findings demonstrate a novel strategy for LASV-Z to hijack the host autophagy machinery to accomplish effective transportation.

KEYWORDS:

• Autophagosome
• CCT2
• cytoskeleton
• lassa virus
• matrix protein
• virus-like particle

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Acknowledgments

This study was supported by the Guangdong Major Project of Basic and Applied Basic Research (No. 2020B0301030007) and Fundamental Research Funds for the Central Universities (No. 2662023PY005). The funders had no conflicts of interest in the study design, data collection and analysis, publication decision, or manuscript preparation.

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We authors declare all data and materials are available on request.

Disclosure statement

The authors declare that they have no competing interests.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2024.2379099.

Additional information

Funding

The work was supported by the Fundamental Research Funds for the Central Universities Guangdong Major Project of Basic and Applied Basic Research [2020B0301030007].