Lysosomal Protein Lamtor1 Controls Innate Immune Responses via Nuclear Translocation of Transcription Factor EB

AbstractThe recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of ongoing global pandemic of COVID-19, may trigger immunosuppression in the early stage and overactive immune response in the late stage of infection; However, the underlying mechanisms are not well understood. Here we demonstrated that the SARS-CoV-2 nucleocapsid (N) protein dually regulated innate immune responses, i.e., the low-dose N protein suppressed type I interferon (IFN-I) signaling and inflammatory cytokines, whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines. Mechanistically, the SARS-CoV-2 N protein dually regulated the phosphorylation and nuclear translocation of IRF3, STAT1, and STAT2. Additionally, low-dose N protein combined with TRIM25 could suppress the ubiquitination and activation of retinoic acid-inducible gene I (RIG-I). Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein, which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses, and development of more effective strategies for controlling COVID-19.

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NSD3 keeps IRF3 active

Journal of Experimental Medicine ◽

10.1084/jem.20171980 ◽

2017 ◽

Vol 214 (12) ◽

pp. 3475-3476

Author(s):

Takashi Mino ◽

Osamu Takeuchi

Keyword(s):

Transcription Factor ◽

Immune Responses ◽

Transcriptional Activity ◽

Innate Immune ◽

Innate Immune Responses

In this issue of JEM, Wang et al. (https://doi.org/10.1084/jem.20170856) show a novel antiviral innate mechanism by which methyltransferase NSD3 directly monomethylates a transcription factor IRF3 and maintains IRF3 phosphorylation to enhance its transcriptional activity, consequently promoting antiviral innate immune responses.

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Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1324140111 ◽

2014 ◽

Vol 111 (7) ◽

pp. 2650-2655 ◽

Cited By ~ 113

Author(s):

A.-M. Bulau ◽

M. F. Nold ◽

S. Li ◽

C. A. Nold-Petry ◽

M. Fink ◽

...

Keyword(s):

Immune Responses ◽

Nuclear Translocation ◽

Innate Immune ◽

Innate Immune Responses ◽

Caspase 1

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Nucleocytoplasmic Trafficking Perturbation Induced by Picornaviruses

Viruses ◽

10.3390/v13071210 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1210

Author(s):

Belén Lizcano-Perret ◽

Thomas Michiels

Keyword(s):

Immune Responses ◽

Nuclear Pore Complex ◽

Viral Genome ◽

Nuclear Translocation ◽

Innate Immune ◽

Nuclear Pore ◽

Innate Immune Responses ◽

Nucleocytoplasmic Trafficking ◽

Host Proteins ◽

Cytoplasmic Proteins

Picornaviruses are positive-stranded RNA viruses. Even though replication and translation of their genome take place in the cytoplasm, these viruses evolved different strategies to disturb nucleocytoplasmic trafficking of host proteins and RNA. The major targets of picornavirus are the phenylalanine-glycine (FG)-nucleoporins, which form a mesh in the central channel of the nuclear pore complex through which protein cargos and karyopherins are actively transported in both directions. Interestingly, while enteroviruses use the proteolytic activity of their 2A protein to degrade FG-nucleoporins, cardioviruses act by triggering phosphorylation of these proteins by cellular kinases. By targeting the nuclear pore complex, picornaviruses recruit nuclear proteins to the cytoplasm, where they increase viral genome translation and replication; they affect nuclear translocation of cytoplasmic proteins such as transcription factors that induce innate immune responses and retain host mRNA in the nucleus thereby preventing cell emergency responses and likely making the ribosomal machinery available for translation of viral RNAs.

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SARS-CoV-2 nucleocapsid protein dually regulates innate immune responses

10.1101/2021.02.17.431755 ◽

2021 ◽

Author(s):

Yinghua Zhao ◽

Liyan Sui ◽

Ping Wu ◽

Wenfang Wang ◽

Guangyun Tan ◽

...

Keyword(s):

Immune Responses ◽

Inflammatory Cytokines ◽

Low Dose ◽

Nuclear Translocation ◽

Early Stage ◽

Innate Immune ◽

High Dose ◽

Type I ◽

Innate Immune Responses ◽

N Protein

ABSTRACTThe recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing global pandemic of COVID-19, may trigger immunosuppression in the early stage and a cytokine storm in the late stage of infection, however, the underlying mechanisms are not well understood. Here we demonstrated that the SARS-CoV-2 nucleocapsid (N) protein dually regulated innate immune responses, i.e., the low-dose N protein suppressed type I interferon (IFN-I) signaling and inflammatory cytokines, whereas high-dose N protein promoted IFN-I signaling and inflammatory cytokines. Mechanistically, the SARS-CoV-2 N protein interacted with the tripartite motif protein 25 (TRIM25), thereby dually regulating the phosphorylation and nuclear translocation of IRF3, STAT1 and STAT2. Additionally, low-dose N protein combined with TRIM25 could suppress retinoic acid-inducible gene I (RIG-I) ubiquitination and activation. Our findings revealed a regulatory mechanism of innate immune responses by the SARS-CoV-2 N protein, which would contribute to understanding the pathogenesis of SARS-CoV-2 and other SARS-like coronaviruses, and development of more effective strategies for controlling COVID-19.

Download Full-text