The nucleolus is the site for inflammatory RNA decay during infection

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

doi:10.1038/s41467-022-32856-2

The nucleolus is the site for inflammatory RNA decay during infection

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

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	5203
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32856-2
Publication status	Published - 2022 Dec

Bibliographical note

Funding Information:
We thank Dr. Victoria Stepanova (Pathology and Laboratory Medicine Perelman School of Medicine at the University of Pennsylvania) for kindly providing full-length wild-type mouse NCL plasmid. We appreciate Junghyun Cho, Mikhail Fomin, Kelly Misare, Dimitrios G Anastasakis, Duncan Claypool, and Amir Manzourolajdad for providing technical support of PAR-CLIP. This work was supported by the Samsung Science & Technology Foundation (SSTF-BA1801-08) and the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and future planning (NRF-2016R1A5A1010764, NRF-2017R1E1A1A01074135, NRF-2022R1A2C3008614, and NRF-2022M3E5F2018597). S.L. was supported by NRF (NRF-2018R1D1A1B07048930) and the National Cancer Center of Korea (NCC-2010170). J.-H.Y. and K.-W.M. were supported by startup fund from Medical University of South Carolina. A.P. and M.H. were supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. J.E.L. was supported by NRF (NRF-2021R1A2C3004572 and NRF-2021R1A4A2001389), J.W.L. and K.-W.M. were supported by NRF (NRF-2019R1C1C1002886 and NRF-2022R1A2C4001528), and T.A.L. was supported by NRF (NRF-2019R1A6A3A01096470 and NRF-2020R1I1A1A01072359). T.A.L., E.A.R., E.L., A.Park, S.K., and J.L.C. were supported by the Brain Korea (BK21) FOUR Program.

Funding Information:
We thank Dr. Victoria Stepanova (Pathology and Laboratory Medicine Perelman School of Medicine at the University of Pennsylvania) for kindly providing full-length wild-type mouse NCL plasmid. We appreciate Junghyun Cho, Mikhail Fomin, Kelly Misare, Dimitrios G Anastasakis, Duncan Claypool, and Amir Manzourolajdad for providing technical support of PAR-CLIP. This work was supported by the Samsung Science & Technology Foundation (SSTF-BA1801-08) and the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and future planning (NRF-2016R1A5A1010764, NRF-2017R1E1A1A01074135, NRF-2022R1A2C3008614, and NRF-2022M3E5F2018597). S.L. was supported by NRF (NRF-2018R1D1A1B07048930) and the National Cancer Center of Korea (NCC-2010170). J.-H.Y. and K.-W.M. were supported by startup fund from Medical University of South Carolina. A.P. and M.H. were supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. J.E.L. was supported by NRF (NRF-2021R1A2C3004572 and NRF-2021R1A4A2001389), J.W.L. and K.-W.M. were supported by NRF (NRF-2019R1C1C1002886 and NRF-2022R1A2C4001528), and T.A.L. was supported by NRF (NRF-2019R1A6A3A01096470 and NRF-2020R1I1A1A01072359). T.A.L., E.A.R., E.L., A.Park, S.K., and J.L.C. were supported by the Brain Korea (BK21) FOUR Program.

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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10.1038/s41467-022-32856-2

Cite this

Lee, T. A., Han, H., Polash, A., Cho, S. K., Lee, J. W., Ra, E. A., Lee, E., Park, A., Kang, S., Choi, J. L., Kim, J. H., Lee, J. E., Min, K. W., Yang, S. W., Hafner, M., Lee, I., Yoon, J. H., Lee, S., & Park, B. (2022). The nucleolus is the site for inflammatory RNA decay during infection. Nature communications, 13(1), [5203]. https://doi.org/10.1038/s41467-022-32856-2

@article{a8f05e983d3e4cbcb68310afcebcfa35,

title = "The nucleolus is the site for inflammatory RNA decay during infection",

abstract = "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.",

author = "Lee, {Taeyun A.} and Heonjong Han and Ahsan Polash and Cho, {Seok Keun} and Lee, {Ji Won} and Ra, {Eun A.} and Eunhye Lee and Areum Park and Sujin Kang and Choi, {Junhee L.} and Kim, {Ji Hyun} and Lee, {Ji Eun} and Min, {Kyung Won} and Yang, {Seong Wook} and Markus Hafner and Insuk Lee and Yoon, {Je Hyun} and Sungwook Lee and Boyoun Park",

note = "Funding Information: We thank Dr. Victoria Stepanova (Pathology and Laboratory Medicine Perelman School of Medicine at the University of Pennsylvania) for kindly providing full-length wild-type mouse NCL plasmid. We appreciate Junghyun Cho, Mikhail Fomin, Kelly Misare, Dimitrios G Anastasakis, Duncan Claypool, and Amir Manzourolajdad for providing technical support of PAR-CLIP. This work was supported by the Samsung Science & Technology Foundation (SSTF-BA1801-08) and the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and future planning (NRF-2016R1A5A1010764, NRF-2017R1E1A1A01074135, NRF-2022R1A2C3008614, and NRF-2022M3E5F2018597). S.L. was supported by NRF (NRF-2018R1D1A1B07048930) and the National Cancer Center of Korea (NCC-2010170). J.-H.Y. and K.-W.M. were supported by startup fund from Medical University of South Carolina. A.P. and M.H. were supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. J.E.L. was supported by NRF (NRF-2021R1A2C3004572 and NRF-2021R1A4A2001389), J.W.L. and K.-W.M. were supported by NRF (NRF-2019R1C1C1002886 and NRF-2022R1A2C4001528), and T.A.L. was supported by NRF (NRF-2019R1A6A3A01096470 and NRF-2020R1I1A1A01072359). T.A.L., E.A.R., E.L., A.Park, S.K., and J.L.C. were supported by the Brain Korea (BK21) FOUR Program. Funding Information: We thank Dr. Victoria Stepanova (Pathology and Laboratory Medicine Perelman School of Medicine at the University of Pennsylvania) for kindly providing full-length wild-type mouse NCL plasmid. We appreciate Junghyun Cho, Mikhail Fomin, Kelly Misare, Dimitrios G Anastasakis, Duncan Claypool, and Amir Manzourolajdad for providing technical support of PAR-CLIP. This work was supported by the Samsung Science & Technology Foundation (SSTF-BA1801-08) and the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and future planning (NRF-2016R1A5A1010764, NRF-2017R1E1A1A01074135, NRF-2022R1A2C3008614, and NRF-2022M3E5F2018597). S.L. was supported by NRF (NRF-2018R1D1A1B07048930) and the National Cancer Center of Korea (NCC-2010170). J.-H.Y. and K.-W.M. were supported by startup fund from Medical University of South Carolina. A.P. and M.H. were supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. J.E.L. was supported by NRF (NRF-2021R1A2C3004572 and NRF-2021R1A4A2001389), J.W.L. and K.-W.M. were supported by NRF (NRF-2019R1C1C1002886 and NRF-2022R1A2C4001528), and T.A.L. was supported by NRF (NRF-2019R1A6A3A01096470 and NRF-2020R1I1A1A01072359). T.A.L., E.A.R., E.L., A.Park, S.K., and J.L.C. were supported by the Brain Korea (BK21) FOUR Program. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-32856-2",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - The nucleolus is the site for inflammatory RNA decay during infection

AU - Lee, Taeyun A.

AU - Han, Heonjong

AU - Polash, Ahsan

AU - Cho, Seok Keun

AU - Lee, Ji Won

AU - Ra, Eun A.

AU - Lee, Eunhye

AU - Park, Areum

AU - Kang, Sujin

AU - Choi, Junhee L.

AU - Kim, Ji Hyun

AU - Lee, Ji Eun

AU - Min, Kyung Won

AU - Yang, Seong Wook

AU - Hafner, Markus

AU - Lee, Insuk

AU - Yoon, Je Hyun

AU - Lee, Sungwook

AU - Park, Boyoun

N1 - Funding Information: We thank Dr. Victoria Stepanova (Pathology and Laboratory Medicine Perelman School of Medicine at the University of Pennsylvania) for kindly providing full-length wild-type mouse NCL plasmid. We appreciate Junghyun Cho, Mikhail Fomin, Kelly Misare, Dimitrios G Anastasakis, Duncan Claypool, and Amir Manzourolajdad for providing technical support of PAR-CLIP. This work was supported by the Samsung Science & Technology Foundation (SSTF-BA1801-08) and the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and future planning (NRF-2016R1A5A1010764, NRF-2017R1E1A1A01074135, NRF-2022R1A2C3008614, and NRF-2022M3E5F2018597). S.L. was supported by NRF (NRF-2018R1D1A1B07048930) and the National Cancer Center of Korea (NCC-2010170). J.-H.Y. and K.-W.M. were supported by startup fund from Medical University of South Carolina. A.P. and M.H. were supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. J.E.L. was supported by NRF (NRF-2021R1A2C3004572 and NRF-2021R1A4A2001389), J.W.L. and K.-W.M. were supported by NRF (NRF-2019R1C1C1002886 and NRF-2022R1A2C4001528), and T.A.L. was supported by NRF (NRF-2019R1A6A3A01096470 and NRF-2020R1I1A1A01072359). T.A.L., E.A.R., E.L., A.Park, S.K., and J.L.C. were supported by the Brain Korea (BK21) FOUR Program. Funding Information: We thank Dr. Victoria Stepanova (Pathology and Laboratory Medicine Perelman School of Medicine at the University of Pennsylvania) for kindly providing full-length wild-type mouse NCL plasmid. We appreciate Junghyun Cho, Mikhail Fomin, Kelly Misare, Dimitrios G Anastasakis, Duncan Claypool, and Amir Manzourolajdad for providing technical support of PAR-CLIP. This work was supported by the Samsung Science & Technology Foundation (SSTF-BA1801-08) and the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and future planning (NRF-2016R1A5A1010764, NRF-2017R1E1A1A01074135, NRF-2022R1A2C3008614, and NRF-2022M3E5F2018597). S.L. was supported by NRF (NRF-2018R1D1A1B07048930) and the National Cancer Center of Korea (NCC-2010170). J.-H.Y. and K.-W.M. were supported by startup fund from Medical University of South Carolina. A.P. and M.H. were supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. J.E.L. was supported by NRF (NRF-2021R1A2C3004572 and NRF-2021R1A4A2001389), J.W.L. and K.-W.M. were supported by NRF (NRF-2019R1C1C1002886 and NRF-2022R1A2C4001528), and T.A.L. was supported by NRF (NRF-2019R1A6A3A01096470 and NRF-2020R1I1A1A01072359). T.A.L., E.A.R., E.L., A.Park, S.K., and J.L.C. were supported by the Brain Korea (BK21) FOUR Program. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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JO - Nature Communications

JF - Nature Communications

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M1 - 5203

ER -

The nucleolus is the site for inflammatory RNA decay during infection

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