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Nat Immunol. 2019 Sep;20(9):1196-1207. doi: 10.1038/s41590-019-0454-6. Epub 2019 Aug 12.

The E3 ubiquitin ligase SPOP controls resolution of systemic inflammation by triggering MYD88 degradation.

Author information

1
Department of Pathology, NYU School of Medicine, New York, NY, USA. maria.guillamot-ruano@nyumc.org.
2
Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA. maria.guillamot-ruano@nyumc.org.
3
Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
4
Department of Pathology, NYU School of Medicine, New York, NY, USA.
5
Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA.
6
Applied Bioinformatics Laboratories, Office of Science & Research, NYU School of Medicine, New York, NY, USA.
7
Department of Microbiology, NYU School of Medicine, New York, NY, USA.
8
The Stowers Institute of Medical Research, Kansas City, MO, USA.
9
Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, KS, USA.
10
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
11
Department of Urology, Weill Cornell Medicine, New York, NY, USA.
12
Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. businol@upenn.edu.
13
Department of Pathology, NYU School of Medicine, New York, NY, USA. iannis.aifantis@nyumc.org.
14
Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY, USA. iannis.aifantis@nyumc.org.

Abstract

The response to systemic infection and injury requires the rapid adaptation of hematopoietic stem cells (HSCs), which proliferate and divert their differentiation toward the myeloid lineage. Significant interest has emerged in understanding the signals that trigger the emergency hematopoietic program. However, the mechanisms that halt this response of HSCs, which is critical to restore homeostasis, remain unknown. Here we reveal that the E3 ubiquitin ligase Speckle-type BTB-POZ protein (SPOP) restrains the inflammatory activation of HSCs. In the absence of Spop, systemic inflammation proceeded in an unresolved manner, and the sustained response in the HSCs resulted in a lethal phenotype reminiscent of hyper-inflammatory syndrome or sepsis. Our proteomic studies decipher that SPOP restricted inflammation by ubiquitinating the innate signal transducer myeloid differentiation primary response protein 88 (MYD88). These findings unearth an HSC-intrinsic post-translational mechanism that is essential for reestablishing homeostasis after emergency hematopoiesis.

PMID:
31406379
DOI:
10.1038/s41590-019-0454-6

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