African swine fever virus (ASFV) continues to pose a severe threat to the global swine industry. This highly lethal DNA virus causes significant economic disruption across several continents. Developing effective antivirals remains challenging because the virus manipulates host cellular processes with high sophistication. Recent research has provided critical insights into ASFV replication mechanisms by identifying how specific host proteins facilitate viral growth.

Specifically, scientists focused on the viral inner envelope protein, p54. This protein plays a vital role in attachment and entry. Using proximity labeling, researchers mapped the interaction between p54 and various host proteins. They identified 257 potential partners in the host cell. Among these, the 60S ribosomal protein L22 (RPL22) emerged as a key regulator. Furthermore, the study used confocal microscopy and co-immunoprecipitation to confirm this interaction. Additionally, functional studies showed that RPL22 acts as a necessary host factor for the virus.

Decoding ASFV Replication Mechanisms and the PERK Pathway

Functional analysis revealed that losing RPL22 significantly restricts the virus. When scientists knocked out RPL22, ASFV replication dropped. Mechanistically, this inhibition occurs because the absence of RPL22 activates the PERK signaling pathway. This pathway belongs to the endoplasmic reticulum stress (ERS) response. Consequently, the host cell environment becomes unfavorable for viral protein synthesis. This finding highlights a novel regulatory mechanism within the complex host-virus interactome. Notably, the study identifies RPL22 as the first ribosomal protein linked to ASFV p54.

Moreover, the study explored pharmacological ways to influence this pathway. Activating the ERS/PERK pathway with drugs like thapsigargin or CCT020312 successfully suppressed the virus. In contrast, inhibiting the pathway using 4-phenylbutyric acid or AMG-PERK 44 promoted replication. Therefore, the ERS pathway represents a promising target for future anti-ASFV therapies. These findings deepen our understanding of viral pathogenesis and offer new avenues for vaccine development. Researchers believe these insights will assist in controlling future outbreaks more effectively.

Frequently Asked Questions

How does the protein p54 contribute to ASFV infection?

The p54 protein is a crucial component of the viral envelope. It helps the virus attach to host cells and facilitates entry and replication. Recent mapping shows it interacts with host proteins like RPL22 to modulate the infection process and hijack cellular machinery.

What is the role of the PERK pathway in ASFV replication mechanisms?

The PERK pathway is a branch of the host cell\'s endoplasmic reticulum stress response. When activated, it restricts the virus\'s ability to multiply. This makes the pathway a potential target for antiviral drugs that can artificially trigger this defense mechanism.

Disclaimer: This content is for informational and educational purposes only and does not constitute medical advice. While it discusses viral mechanisms in animal health research, the principles of virology and pharmacology mentioned are strictly academic. Refer to the latest local and national guidelines for clinical practice.

References

Li P et al. Loss of Ribosomal Protein RPL22 Restricts African Swine Fever Virus Replication by Inducing PERK-Dependent ER Stress. Emerg Microbes Infect. 2026 May 23. doi: 10.1080/22221751.2026.2678665. PMID: 42175753.

Pannhorst K et al. The non-classical major histocompatibility complex II protein SLA-DM is crucial for African swine fever virus replication. Sci Rep. 2023;13(1):10342. doi: 10.1038/s41598-023-37505-w.

Zhang A et al. Quantitative proteomic analysis identifies the unfolded protein response as a host pathway co-opted by ASFV to promote replication. mBio. 2025;16(6):e02345-25.