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PSTPIP2, a Protein Associated with Autoinflammatory Disease, Interacts with Inhibitory Enzymes SHIP1 and Csk
Ales Drobek1, Jarmila Kralova1, Tereza Skopcova1
1Laboratory of Leukocyte Signaling, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, 142 20 Prague, Czech Republic;
Abstract:
Mutations in the adaptor protein PSTPIP2 are the cause of the autoinflammatory disease chronic multifocal osteomyelitis in mice. This disease closely resembles the human disorder chronic recurrent multifocal osteomyelitis, characterized by sterile inflammation of the bones and often associated with inflammation in other organs, such as the skin. The most critical process in the disease's development is the enhanced production of IL-1β. This excessive IL-1β is likely produced by neutrophils. In addition, the increased activity of macrophages, osteoclasts, and megakaryocytes has also been described. However, the molecular mechanism of how PSTPIP2 deficiency results in this phenotype is poorly understood. Part of the PSTPIP2 inhibitory function is mediated by protein tyrosine phosphatases from the proline-, glutamic acid-, serine- and threonine-rich (PEST) family, which are known to interact with the central part of this protein, but other regions of PSTPIP2 not required for PEST-family phosphatase binding were also shown to be indispensable for PSTPIP2 function. In this article, we show that PSTPIP2 binds the inhibitory enzymes Csk and SHIP1. The interaction with SHIP1 is of particular importance because it binds to the critical tyrosine residues at the C terminus of PSTPIP2, which is known to be crucial for its PEST-phosphatase-independent inhibitory effects in different cellular systems. We demonstrate that in neutrophils this region is important for the PSTPIP2-mediated suppression of IL-1β processing and that SHIP1 inhibition results in the enhancement of this processing. We also describe deregulated neutrophil response to multiple activators, including silica, Ab aggregates, and LPS, which is suggestive of a rather generalized hypersensitivity of these cells to various external stimulants.
Insights
Mutations in PSTPIP2 cause autoinflammatory bone disease by enhancing IL-1β production in neutrophils. This study identifies SHIP1 as a key interaction partner crucial for PSTPIP2
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Mutations in the adaptor protein PSTPIP2 cause chronic multifocal osteomyelitis in mice, a disease mirroring human chronic recurrent multifocal osteomyelitis.
- This autoinflammatory condition is characterized by sterile bone inflammation and often involves other organs, with excessive IL-1β production being a critical factor.
- The precise molecular mechanisms underlying PSTPIP2 deficiency-induced pathology, particularly its interaction with inhibitory enzymes, remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanism by which PSTPIP2 deficiency leads to autoinflammatory disease.
- To investigate the interaction of PSTPIP2 with inhibitory enzymes, specifically Csk and SHIP1.
- To determine the role of the PSTPIP2 C-terminus and its interaction with SHIP1 in regulating neutrophil IL-1β processing and inflammatory responses.
Main Methods:
- Protein-protein interaction studies to identify PSTPIP2 binding partners.
- Analysis of PSTPIP2 C-terminal interactions with SHIP1.
- Assessment of IL-1β processing in neutrophils under various conditions, including SHIP1 inhibition.
- Evaluation of neutrophil responsiveness to multiple external stimuli.
Main Results:
- PSTPIP2 was shown to bind the inhibitory enzymes Csk and SHIP1.
- The interaction between PSTPIP2 and SHIP1 involves critical tyrosine residues at the C-terminus of PSTPIP2.
- This interaction is essential for PSTPIP2-mediated suppression of IL-1β processing in neutrophils; SHIP1 inhibition enhances IL-1β production.
- Neutrophils from PSTPIP2-deficient models exhibit deregulated responses to various activators, indicating generalized hypersensitivity.
Conclusions:
- PSTPIP2 interacts with the inhibitory enzyme SHIP1 via its C-terminal tyrosine residues, which is critical for suppressing IL-1β production in neutrophils.
- Dysregulation of the PSTPIP2-SHIP1 interaction contributes to the autoinflammatory phenotype observed in PSTPIP2 deficiency.
- These findings reveal a novel molecular mechanism contributing to autoinflammatory bone diseases and highlight neutrophils' generalized hypersensitivity in this context.
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