Publication

USP18 lack in microglia causes destructive interferonopathy of the mouse brain

Goldmann, T., Zeller, N., Raasch, J., Kierdorf, K., Frenzel, K., Ketscher, L., Basters, A., Staszewski, O., Brendecke, S. M., Spiess, A., Tay, T. L., Kreutz, C., Timmer, J., Mancini, G. M. S., Blank, T., Fritz, G., Biber, K., Lang, R., Malo, D., Merkler, D., Heikenwaelder, M., Knobeloch, K-P. & Prinz, M., 12-Jun-2015, In : The EMBO Journal. 34, 12, p. 1612-1629 18 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Goldmann, T., Zeller, N., Raasch, J., Kierdorf, K., Frenzel, K., Ketscher, L., ... Prinz, M. (2015). USP18 lack in microglia causes destructive interferonopathy of the mouse brain. The EMBO Journal, 34(12), 1612-1629. https://doi.org/10.15252/embj.201490791

Author

Goldmann, Tobias ; Zeller, Nicolas ; Raasch, Jenni ; Kierdorf, Katrin ; Frenzel, Kathrin ; Ketscher, Lars ; Basters, Anja ; Staszewski, Ori ; Brendecke, Stefanie M. ; Spiess, Alena ; Tay, Tuan Leng ; Kreutz, Clemens ; Timmer, Jens ; Mancini, Grazia M. S. ; Blank, Thomas ; Fritz, Guenter ; Biber, Knut ; Lang, Roland ; Malo, Danielle ; Merkler, Doron ; Heikenwaelder, Mathias ; Knobeloch, Klaus-Peter ; Prinz, Marco. / USP18 lack in microglia causes destructive interferonopathy of the mouse brain. In: The EMBO Journal. 2015 ; Vol. 34, No. 12. pp. 1612-1629.

Harvard

Goldmann, T, Zeller, N, Raasch, J, Kierdorf, K, Frenzel, K, Ketscher, L, Basters, A, Staszewski, O, Brendecke, SM, Spiess, A, Tay, TL, Kreutz, C, Timmer, J, Mancini, GMS, Blank, T, Fritz, G, Biber, K, Lang, R, Malo, D, Merkler, D, Heikenwaelder, M, Knobeloch, K-P & Prinz, M 2015, 'USP18 lack in microglia causes destructive interferonopathy of the mouse brain', The EMBO Journal, vol. 34, no. 12, pp. 1612-1629. https://doi.org/10.15252/embj.201490791

Standard

USP18 lack in microglia causes destructive interferonopathy of the mouse brain. / Goldmann, Tobias; Zeller, Nicolas; Raasch, Jenni; Kierdorf, Katrin; Frenzel, Kathrin; Ketscher, Lars; Basters, Anja; Staszewski, Ori; Brendecke, Stefanie M.; Spiess, Alena; Tay, Tuan Leng; Kreutz, Clemens; Timmer, Jens; Mancini, Grazia M. S.; Blank, Thomas; Fritz, Guenter; Biber, Knut; Lang, Roland; Malo, Danielle; Merkler, Doron; Heikenwaelder, Mathias; Knobeloch, Klaus-Peter; Prinz, Marco.

In: The EMBO Journal, Vol. 34, No. 12, 12.06.2015, p. 1612-1629.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Goldmann T, Zeller N, Raasch J, Kierdorf K, Frenzel K, Ketscher L et al. USP18 lack in microglia causes destructive interferonopathy of the mouse brain. The EMBO Journal. 2015 Jun 12;34(12):1612-1629. https://doi.org/10.15252/embj.201490791


BibTeX

@article{e0b22a92a2f149ae9ea65a4aa9efe554,
title = "USP18 lack in microglia causes destructive interferonopathy of the mouse brain",
abstract = "Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called {"}microgliopathies{"}. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. Here, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence. We further found that microglial Usp18 negatively regulates the activation of Stat1 and concomitant induction of interferon-induced genes, thereby terminating IFN signaling. The Usp18-mediated control was independent from its catalytic activity but instead required the interaction with Ifnar2. Additionally, the absence of Ifnar1 restored microglial activation, indicating a tonic IFN signal which needs to be negatively controlled by Usp18 under non-diseased conditions. These results identify Usp18 as a critical negative regulator of microglia activation and demonstrate a protective role of Usp18 for microglia function by regulating the Ifnar pathway. The findings establish Usp18 as a new molecule preventing destructive microgliopathy.",
keywords = "EAE, microglia, multiple sclerosis, type I interferon, Usp18, NF-KAPPA-B, CENTRAL-NERVOUS-SYSTEM, DEUBIQUITINATING ENZYME CYLD, MULTIPLE-SCLEROSIS, ISOPEPTIDASE ACTIVITY, ALZHEIMERS-DISEASE, COMMON VARIANTS, ACTIVATION, CELLS, GENE",
author = "Tobias Goldmann and Nicolas Zeller and Jenni Raasch and Katrin Kierdorf and Kathrin Frenzel and Lars Ketscher and Anja Basters and Ori Staszewski and Brendecke, {Stefanie M.} and Alena Spiess and Tay, {Tuan Leng} and Clemens Kreutz and Jens Timmer and Mancini, {Grazia M. S.} and Thomas Blank and Guenter Fritz and Knut Biber and Roland Lang and Danielle Malo and Doron Merkler and Mathias Heikenwaelder and Klaus-Peter Knobeloch and Marco Prinz",
year = "2015",
month = "6",
day = "12",
doi = "10.15252/embj.201490791",
language = "English",
volume = "34",
pages = "1612--1629",
journal = "The EMBO Journal",
issn = "0261-4189",
publisher = "Wiley",
number = "12",

}

RIS

TY - JOUR

T1 - USP18 lack in microglia causes destructive interferonopathy of the mouse brain

AU - Goldmann, Tobias

AU - Zeller, Nicolas

AU - Raasch, Jenni

AU - Kierdorf, Katrin

AU - Frenzel, Kathrin

AU - Ketscher, Lars

AU - Basters, Anja

AU - Staszewski, Ori

AU - Brendecke, Stefanie M.

AU - Spiess, Alena

AU - Tay, Tuan Leng

AU - Kreutz, Clemens

AU - Timmer, Jens

AU - Mancini, Grazia M. S.

AU - Blank, Thomas

AU - Fritz, Guenter

AU - Biber, Knut

AU - Lang, Roland

AU - Malo, Danielle

AU - Merkler, Doron

AU - Heikenwaelder, Mathias

AU - Knobeloch, Klaus-Peter

AU - Prinz, Marco

PY - 2015/6/12

Y1 - 2015/6/12

N2 - Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called "microgliopathies". However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. Here, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence. We further found that microglial Usp18 negatively regulates the activation of Stat1 and concomitant induction of interferon-induced genes, thereby terminating IFN signaling. The Usp18-mediated control was independent from its catalytic activity but instead required the interaction with Ifnar2. Additionally, the absence of Ifnar1 restored microglial activation, indicating a tonic IFN signal which needs to be negatively controlled by Usp18 under non-diseased conditions. These results identify Usp18 as a critical negative regulator of microglia activation and demonstrate a protective role of Usp18 for microglia function by regulating the Ifnar pathway. The findings establish Usp18 as a new molecule preventing destructive microgliopathy.

AB - Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called "microgliopathies". However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. Here, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence. We further found that microglial Usp18 negatively regulates the activation of Stat1 and concomitant induction of interferon-induced genes, thereby terminating IFN signaling. The Usp18-mediated control was independent from its catalytic activity but instead required the interaction with Ifnar2. Additionally, the absence of Ifnar1 restored microglial activation, indicating a tonic IFN signal which needs to be negatively controlled by Usp18 under non-diseased conditions. These results identify Usp18 as a critical negative regulator of microglia activation and demonstrate a protective role of Usp18 for microglia function by regulating the Ifnar pathway. The findings establish Usp18 as a new molecule preventing destructive microgliopathy.

KW - EAE

KW - microglia

KW - multiple sclerosis

KW - type I interferon

KW - Usp18

KW - NF-KAPPA-B

KW - CENTRAL-NERVOUS-SYSTEM

KW - DEUBIQUITINATING ENZYME CYLD

KW - MULTIPLE-SCLEROSIS

KW - ISOPEPTIDASE ACTIVITY

KW - ALZHEIMERS-DISEASE

KW - COMMON VARIANTS

KW - ACTIVATION

KW - CELLS

KW - GENE

U2 - 10.15252/embj.201490791

DO - 10.15252/embj.201490791

M3 - Article

VL - 34

SP - 1612

EP - 1629

JO - The EMBO Journal

JF - The EMBO Journal

SN - 0261-4189

IS - 12

ER -

ID: 20973201