The nucleolus is the site for inflammatory RNA decay during infection.

Nature communications 2022 Sep 03

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Inflammatory cytokines are key signaling molecules that can promote an immune response, thus their RNA turnover must be tightly controlled during infection. Most studies investigate the RNA decay pathways in the cytosol or nucleoplasm but never focused on the nucleolus. Although this organelle has well-studied roles in ribosome biogenesis and cellular stress sensing, the mechanism of RNA decay within the nucleolus is not completely understood. Here, we report that the nucleolus is an essential site of inflammatory pre-mRNA instability during infection. RNA-sequencing analysis reveals that not only do inflammatory genes have higher intronic read densities compared with non-inflammatory genes, but their pre-mRNAs are highly enriched in nucleoli during infection. Notably, nucleolin (NCL) acts as a guide factor for recruiting cytosine or uracil (C/U)-rich sequence-containing inflammatory pre-mRNAs and the Rrp6-exosome complex to the nucleolus through a physical interaction, thereby enabling targeted RNA delivery to Rrp6-exosomes and subsequent degradation. Consequently, Ncl depletion causes aberrant hyperinflammation, resulting in a severe lethality in response to LPS. Importantly, the dynamics of NCL post-translational modifications determine its functional activity in phases of LPS. This process represents a nucleolus-dependent pathway for maintaining inflammatory gene expression integrity and immunological homeostasis during infection. © 2022. The Author(s).

Citation

Taeyun A Lee, Heonjong Han, Ahsan Polash, Seok Keun Cho, Ji Won Lee, Eun A Ra, Eunhye Lee, Areum Park, Sujin Kang, Junhee L Choi, Ji Hyun Kim, Ji Eun Lee, Kyung-Won Min, Seong Wook Yang, Markus Hafner, Insuk Lee, Je-Hyun Yoon, Sungwook Lee, Boyoun Park. The nucleolus is the site for inflammatory RNA decay during infection. Nature communications. 2022 Sep 03;13(1):5203