Absence of SHIP-1 Results in Constitutive Phosphorylation of Tank-Binding Kinase 1 and Enhanced TLR3-Dependent IFN-β Production
Open accessAbstract
Autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, result from a loss of tolerance to self-antigens and immune-mediated injury precipitated by the overproduction of type I IFN and inflammatory cytokines. We have identified the inositol 5′ phosphatase SHIP-1 as a negative regulator of TLR3-induced type I IFN production. SHIP-1–deficient macrophages display enhanced TLR-induced IFN-β production, and overexpression of SHIP-1 negatively regulates the ability of TLR3 and its adaptor, Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β, to induce IFN-β promoter activity, indicating that SHIP-1 negatively regulates TLR-induced IFN-β production. Further dissection of the IFN-β pathway implicates TANK-binding kinase 1 (TBK1) as the target for SHIP-1. Critically, in the absence of SHIP-1, TBK1 appears to be hyperphosphorylated both in unstimulated cells and following TLR3 stimulation. In addition, TBK1 appears to be constitutively associated with Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β and TNFR-associated factor 3 in SHIP-1 deficient cells, whereas in wild-type cells this association is inducible following TLR3 stimulation. In support of a role for SHIP-1 in regulating complex formation, confocal microscopy demonstrates that TBK1 distribution in the cell is significantly altered in SHIP-1–deficient cells, with more prominent endosomal staining observed, compared with wild-type controls. Taken together, our results point to SHIP-1 as a critical negative regulator of IFN-β production downstream of TLR3 through the regulation of TBK1 localization and activity.
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Dysfunction of SHIP1 has been associated with a spectrum of diseases, including AD, AML, SLE, RA.
“As such, dysfunction of SHIP1 has been associated with a spectrum of diseases, including Alzheimer’s disease (AD), acute myeloid leukemia (AML) and autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)3–6.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [3]
The Discussion (page unavailable) links defects in immune regulation to SLE and rheumatoid arthritis and describes SHIP-1 as a negative regulator of relevant signaling. It does not establish a direct clinical association between SHIP1 dysfunction and those diseases, and the searched passages do not address Alzheimer’s disease or acute myeloid leukemia. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSHIP1 deficiency has been implicated in various diseases of the immune system, such as acute myeloid leukemia (AML) and systemic lupus erythematosus (SLE).
“SHIP1 deficiency has been implicated in various diseases of the immune system, such as acute myeloid leukemia (AML) and systemic lupus erythematosus (SLE)3–5.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [3]
The Discussion (page unavailable) links SHIP-1 regulation of IFN-β to a potential role in SLE and describes implications for autoimmune disorders. It does not establish SHIP-1 deficiency in SLE patients, and no passage found in our copy addresses acute myeloid leukemia (searched: acute myeloid leukemia, AML). (LLM, conf=0.85)
Experimental — accuracy not yet measuredSHIP1 is primarily expressed in myeloid cells.
“SHIP1 is primarily expressed in myeloid cells”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [3]
The Cell culture and Results sections study SHIP-1 in bone marrow-derived macrophages, but do not compare its expression across cell types. Searches for “myeloid” and for SHIP-1 expression in hematopoietic or myeloid cells found no passage establishing that it is primarily expressed in myeloid cells. The indexed passages provide no page numbers. (LLM, conf=0.72)
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SHIP1 regulates TREM2 signalling and macrophage functions in a hiPSC ‐derived model
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- Authors
- Gabhann, J. N., Higgs, R., Brennan, K., Thomas, W., Damen, J. E., Ben Larbi, N., Krystal, G., & Jefferies, C. A.
- Affiliations
- Royal College of Surgeons in Ireland (IE)
- Stemcell Technologies (CA)
- Molecular and Cellular Therapeutics, Royal College of Surgeons, Ireland Research Institute
- BC Cancer Agency (CA)
- Corresponding author
- Higgs, Rowan
- Brennan, Kiva
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-03-01
- Volume
- 184
- Issue
- 5
- Pages
- 2314-2320
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1642847216
- Cited by
- 81
- References
- 52
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 4 · 2020: 4 · 2019: 3 · 2018: 6 · 2017: 4 · 2016: 2 · 2015: 9 · 2014: 5 · 2013: 9 · 2012: 9
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Health Research Board
- European Commission
- Higher Education Authority
- Science Foundation Ireland
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Keywords
- SHIP1, TBK1, TBK1 phosphorylation, TLR3 signaling, type I interferon, interferon-beta, TRAF3, TRIF, macrophages, inositol polyphosphate 5-phosphatase, endosomal localization, autoimmune disease, negative regulation of innate immunity
- MeSH terms
- Inositol Polyphosphate 5-Phosphatases, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Imiquimod, Aminoquinolines, Animals, Bone Marrow Cells, Cell Line, Flow Cytometry, Humans, Lipopolysaccharides, Macrophages, Phosphoric Monoester Hydrolases, Phosphorylation, Promoter Regions, Genetic, Protein Binding, Blotting, Western, Cytokines, NF-kappa B, Interferon-beta, Protein Serine-Threonine Kinases, Mice, Knockout, Microscopy, Confocal, Inflammation Mediators, Reverse Transcriptase Polymerase Chain Reaction, Toll-Like Receptor 3, Mice
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