Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 27, Pages 9834-9839Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1407898111
Keywords
TP53BP2; TLR4; multiple sclerosis
Categories
Funding
- Ludwig Institute for Cancer Research Ltd.
- National Institutes of Health-Oxford Scholars Program
- Medical Research Council [MR/J000930/1]
- Fondation Contre le Cancer [IAP P7/43 BeMGI, ARC 10/15-027]
- St. John's College
- European Union Neurobid Consortium
- National Institutes of Health [R01 NS-42253]
- Cancer Research-United Kingdom Oxford Cancer Centre Development Fund
- Oxford National Institute for Health Research Biomedical Research Centre
- Biotechnology and Biological Sciences Research Council [BB/I021833/1] Funding Source: researchfish
- Medical Research Council [G0900901, MR/J000930/1, MR/L022656/1] Funding Source: researchfish
- BBSRC [BB/I021833/1] Funding Source: UKRI
- MRC [MR/J000930/1, G0900901, MR/L022656/1] Funding Source: UKRI
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Inflammation and loss of cell polarity play pivotal roles in neurodegeneration and cancer. A central question in both diseases is how the loss of cell polarity is sensed by cell death machinery. Here, we identify apoptosis-stimulating protein of p53 with signature sequences of ankyrin repeat-, SH3 domain-, and proline-rich region-containing protein 2 (ASPP2), a haploinsufficient tumor suppressor, activator of p53, and regulator of cell polarity, as a transcriptional target of signal transducer and activator of transcription 1 (STAT1). LPS induces ASPP2 expression in murine macrophage and microglial cell lines, a human monocyte cell line, and primary human astrocytes in vitro. LPS and IFNs induce ASPP2 transcription through an NF-kappa B RELA/p65-independent but STAT1-dependent pathway. In an LPS-induced maternal inflammation mouse model, LPS induces nuclear ASPP2 in vivo at the blood-cerebral spinal fluid barrier (the brain's barrier to inflammation), and ASPP2 mediates LPS-induced apoptosis. Consistent with the role of ASPP2 as a gatekeeper to inflammation, ASPP2-deficient brains possess enhanced neuroinflammation. Elevated ASPP2 expression is also observed in mouse models and human neuroinflammatory disease tissue, where ASPP2 was detected in GFAP-expressing reactive astrocytes that coexpress STAT1. Because the ability of ASPP2 to maintain cellular polarity is vital to CNS development, our findings suggest that the identified STAT1/ASPP2 pathway may connect tumor suppression and cell polarity to neuroinflammation.
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