Biozentrum, University of Basel, Basel, Switzerland.
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Eur J Immunol. 2018 Feb;48(2):230-238. doi: 10.1002/eji.201746947. Epub 2017 Dec 6.
Pyrin, encoded by the MEFV gene, is an intracellular pattern recognition receptor that assembles inflammasome complexes in response to pathogen infections. Mutations in the MEFV gene have been linked to autoinflammatory diseases such as familial Mediterranean fever (FMF) or pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). Recent insights have now revealed how pyrin is activated during infection, providing a molecular basis for the understanding of such disease-causing mutations in pyrin. Interestingly, pyrin does not directly recognize molecular patterns (pathogen- or host-derived danger molecules), but rather responds to disturbances in cytoplasmic homeostasis caused by the infection. In the case of pyrin, these perturbations, recently defined as 'homeostasis-altering molecular processes' (HAMPs), are processes leading to the inactivation of the RhoA GTPase. This review attempts to combine early observation and findings with the most recent discoveries on how pyrin detects inactivation of RhoA to shed light on the function and mechanism of pyrin activation.
Pyrin，由 MEFV 基因编码，是一种细胞内模式识别受体，可在病原体感染时组装炎症小体复合物。MEFV 基因的突变与自身炎症性疾病有关，如家族性地中海热 (FMF) 或伴中性粒细胞皮肤病的 pyrin 相关自身炎症 (PAAND)。最近的研究揭示了 pyrin 在感染过程中是如何被激活的，为理解 pyrin 中导致这些疾病的突变提供了分子基础。有趣的是，pyrin 并不直接识别分子模式（病原体或宿主来源的危险分子），而是对感染引起的细胞质内稳态紊乱做出反应。在 pyrin 的情况下，这些最近被定义为“改变内稳态的分子过程”（HAMPs）的扰动，是导致 RhoA GTPase 失活的过程。本文试图将早期观察和发现与 pyrin 检测 RhoA 失活的最新发现结合起来，以阐明 pyrin 激活的功能和机制。
