Laboratory of Molecular Basis of Altered Immune Homeostasis, Imagine Institute, Université Paris Cité, Institut National de la Santé et de la Recherche Médicale (INSERM) Unite Mixte de Recherche (UMR)1163, Paris, France.
Centre de Recherche sur l'Inflammation, Université Paris Cité, INSERM UMR1149, Centre National de la Recherche Scientifique (CNRS) EMR8252, Faculté de Médecine site Bichat, Paris, France.
J Allergy Clin Immunol. 2022 Sep;150(3):676-689. doi: 10.1016/j.jaci.2022.04.009. Epub 2022 Apr 22.
Mast cells (MCs) are key effectors of the allergic response. Following the cross-linking of IgE receptors (FcεRIs), they release crucial inflammatory mediators through degranulation. Although degranulation depends critically on secretory granule (SG) trafficking toward the plasma membrane, the molecular machinery underlying this transport has not been fully characterized.
This study analyzed the function of Rab44, a large, atypical Rab guanosine triphosphatase highly expressed in MC, in the MC degranulation process.
Murine knockout (KO) mouse models (KO and DKO) were used to perform passive cutaneous anaphylaxis experiments and analyze granule translocation in bone marrow-derived MCs during degranulation.
This study demonstrate that mice lacking Rab44 (KO) in their bone marrow-derived MCs are impaired in their ability to translocate and degranulate SGs at the plasma membrane on FcεRI stimulation. Accordingly, KO mice were less sensitive to IgE-mediated passive cutaneous anaphylaxis in vivo. A lack of Rab44 did not impair early FcεRI-stimulated signaling pathways, microtubule reorganization, lipid mediator release, or cytokine secretion. Mechanistically, Rab44 appears to interact with and function as part of the previously described kinesin-1-dependent transport pathway.
These results highlight a novel role of Rab44 as a regulator of SG transport during degranulation and anaphylaxis acting through the kinesin-1-dependent microtubule transport machinery. Rab44 can thus be considered a potential target for modulating MC degranulation and inhibiting IgE-mediated allergic reactions.
肥大细胞（MCs）是过敏反应的关键效应物。在 IgE 受体（FcεRIs）交联后，它们通过脱颗粒释放关键的炎症介质。尽管脱颗粒严重依赖于分泌颗粒（SG）向质膜的运输，但这种运输的分子机制尚未完全阐明。
本研究分析了在 MC 中高度表达的大型非典型 Rab GTPase Rab44 在 MC 脱颗粒过程中的功能。
使用小鼠敲除（KO）鼠模型（KO 和 DKO）进行被动皮肤过敏反应实验，并在脱颗粒过程中分析骨髓来源的 MC 中的颗粒易位。
本研究表明，骨髓来源的 MC 中缺乏 Rab44 的小鼠（KO）在 FcεRI 刺激下，其 SG 在质膜上的易位和脱颗粒能力受损。相应地，KO 小鼠对 IgE 介导的体内被动皮肤过敏反应的敏感性降低。Rab44 的缺乏并不影响早期 FcεRI 刺激的信号通路、微管重排、脂质介质释放或细胞因子分泌。从机制上讲，Rab44 似乎与先前描述的依赖于驱动蛋白-1 的运输途径相互作用并作为其一部分发挥作用。
这些结果强调了 Rab44 在脱颗粒和过敏反应期间作为 SG 运输调节剂的新作用，通过依赖于驱动蛋白-1 的微管运输机制发挥作用。因此，Rab44 可以被认为是调节 MC 脱颗粒和抑制 IgE 介导的过敏反应的潜在靶标。
