Expression of RNautophagy/DNautophagy-related genes is regulated under control of an innate immune receptor

ABSTRACT

Double-stranded RNA (dsRNA) is a molecular pattern uniquely produced in cells infected with various viruses as a product or byproduct of replication. Cells detect such molecules, which indicate non-self invasion, and induce diverse immune responses to eliminate them. The degradation of virus-derived molecules can also play a role in the removal of pathogens and suppression of their replication. RNautophagy and DNautophagy are cellular degradative pathways in which RNA and DNA are directly imported into a hydrolytic organelle, the lysosome. Two lysosomal membrane proteins, SIDT2 and LAMP2C, mediate nucleic acid uptake via this pathway. Here, we showed that the expression of both SIDT2 and LAMP2C is selectively upregulated during the intracellular detection of poly(I:C), a synthetic analog of dsRNA that mimics viral infection. The upregulation of these two gene products upon poly(I:C) introduction was transient and synchronized. We also observed that the induction of SIDT2 and LAMP2C expression by poly(I:C) was dependent on MDA5, a cytoplasmic innate immune receptor that directly recognizes poly(I:C) and induces various antiviral responses. Finally, we showed that lysosomes can target viral RNA for degradation via RNautophagy and may suppress viral replication. Our results revealed a novel degradative pathway in cells as a downstream component of the innate immune response and provided evidence suggesting that the degradation of viral nucleic acids via RNautophagy/DNautophagy contributes to the suppression of viral replication.

KEYWORDS:

• Lysosome
• RNautophagy
• DNautophagy
• PAMPs
• Double-stranded RNA
• PRRs
• immune response
• innate immunity
• virus infection
• virus replication

Acknowledgments

We thank Yoshiyuki Ohshima, Yoshiaki Furuya, Natsumi Takeyama, Aki Nagao, and Shizuka Hayashi for technical assistance.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data generated or analysed in this study are available from the corresponding authors on reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15476286.2023.2291610

Additional information

Funding

This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (14J08223, 17J10610, 21K15367, and 23K14453 to Y.F.; 16H05146, 16H01211, and 19H05710 to T.K.), ACT-X from Japan Science and Technology Agency (JPMJAX222H to Y.F.), and research grants from the Takeda Science Foundation (to Y.F.).