Tuning IgE: IgE-Associating Molecules and Their Effects on IgE-Dependent Mast Cell Reactions

The recent emergence of anti-immunoglobulin E (IgE) drugs and their candidates for humans has endorsed the significance of IgE-dependent pathways in allergic disorders. IgE is distributed locally in the tissues or systemically to confer a sensory mechanism in a domain of adaptive immunity to the otherwise innate type of effector cells, namely, mast cells and basophils. Bound on the high-affinity IgE receptor FcεRI, IgE enables fast memory responses against revisiting threats of venoms, parasites, and bacteria. However, the dysregulation of IgE-dependent reactions leads to potentially life-threatening allergic diseases, such as asthma and anaphylaxis. Therefore, reactivity of the IgE sensor is fine-tuned by various IgE-associating molecules. In this review, we discuss the mechanistic basis for how IgE-dependent mast cell activation is regulated by the IgE-associating molecules, including the newly developed therapeutic candidates

Mucosal Mast Cells as Key Effector Cells in Food Allergies

Mucosal mast cells (MMCs) localized in the intestinal mucosa play a key role in the development of IgE-mediated food allergies. Recent advances have revealed that MMCs are a distinctly different population from connective tissue mast cells localized in skin and other connective tissues. MMCs are inducible and transient cells that arise from bone marrow-derived mast cell progenitors, and their numbers increase rapidly during mucosal allergic inflammation. However, the mechanism of the dramatic expansion of MMCs and their cell functions are not well understood. Here, we review recent findings on the mechanisms of MMC differentiation and expansion, and we discuss the potential for the inducers of differentiation and expansion to serve as targets for food allergy therapy. In addition, we also discuss the mechanism by which oral immunotherapy, a promising treatment for food allergy patients, induces unresponsiveness to food allergens and the roles of MMCs in this process. Research focusing on MMCs should provide useful information for understanding the underlying mechanisms of food allergies in order to further advance the treatment of food allergies

APC(CDH1) targets MgcRacGAP for destruction in the late M phase.

Male germ cell RacGTPase activating protein (MgcRacGAP) is an important regulator of the Rho family GTPases--RhoA, Rac1, and Cdc42--and is indispensable in cytokinesis and cell cycle progression. Inactivation of RhoA by phosphorylated MgcRacGAP is an essential step in cytokinesis. MgcRacGAP is also involved in G1-S transition and nuclear transport of signal transducer and activator of transcription 3/5 (STAT3/5). Expression of MgcRacGAP is strictly controlled in a cell cycle-dependent manner. However, the underlying mechanisms have not been elucidated.Using MgcRacGAP deletion mutants and the fusion proteins of full-length or partial fragments of MgcRacGAP to mVenus fluorescent protein, we demonstrated that MgcRacGAP is degraded by the ubiquitin-proteasome pathway in the late M to G1 phase via APC(CDH1). We also identified the critical region for destruction located in the C-terminus of MgcRacGAP, AA537-570, which is necessary and sufficient for CDH1-mediated MgcRacGAP destruction. In addition, we identified a PEST domain-like structure with charged residues in MgcRacGAP and implicate it in effective ubiquitination of MgcRacGAP.Our findings not only reveal a novel mechanism for controlling the expression level of MgcRacGAP but also identify a new target of APC(CDH1). Moreover our results identify a C-terminal region AA537-570 of MgcRacGAP as its degron