WIP regulates signaling via the high affinity receptor for immunoglobulin E in mast cells

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Wiskott-Aldrich syndrome protein-interacting protein (WIP) stabilizes actin filaments and is vital for immunoreceptor signaling in T and B cells.
• The high-affinity IgE receptor (FcεRI) pathway in mast cells orchestrates allergic responses through signal transduction and cytoskeletal changes.

Purpose of the Study:

• To investigate the role of WIP in signaling pathways downstream of FcεRI in mast cells.
• To elucidate WIP's function in mast cell degranulation, cytokine secretion, and actin cytoskeleton regulation following FcεRI ligation.

Main Methods:

• Generated and utilized WIP-deficient bone marrow-derived mast cells (BMMCs).
• Stimulated BMMCs via FcεRI ligation and assessed degranulation, IL-6 secretion, calcium mobilization, and protein phosphorylation (Syk, PLCγ2, JNK).
• Analyzed Syk protein levels, WIP-Syk association, and actin cytoskeleton dynamics (protrusion formation, kinetics of actin/cell shape changes).

Main Results:

• WIP-deficient BMMCs showed impaired degranulation and IL-6 secretion upon FcεRI stimulation.
• Key signaling events, including calcium mobilization and Syk/PLCγ2/JNK phosphorylation, were reduced in WIP-deficient BMMCs.
• WIP associates with Syk post-FcεRI ligation, inhibiting Syk degradation and maintaining Syk levels; WIP deficiency led to diminished Syk levels.
• While basic actin network and protrusion formation were intact, the kinetics of actin and cell shape changes were altered in WIP-deficient BMMCs.

Conclusions:

• WIP plays a significant role in FcεRI-mediated mast cell activation.
• WIP regulates mast cell function by controlling Syk protein levels and modulating actin cytoskeleton rearrangement kinetics.
• These findings identify WIP as a key regulator in the FcεRI signaling pathway, impacting allergic responses.