Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Centre Intégré Universitaire de Santé et de Services Sociaux (CIUSSS) de l'Est-de-l'Île de Montreal, Montreal, QC, Canada.
Department of Medicine, Université de Montréal, Montréal, QC, Canada.
Front Immunol. 2024 Apr 12;15:1395035. doi: 10.3389/fimmu.2024.1395035. eCollection 2024.
Inflammation control is critical during the innate immune response. Such response is triggered by the detection of molecules originating from pathogens or damaged host cells by pattern-recognition receptors (PRRs). PRRs subsequently initiate intra-cellular signalling through different pathways, resulting in i) the production of inflammatory cytokines, including type I interferon (IFN), and ii) the initiation of a cascade of events that promote both immediate host responses as well as adaptive immune responses. All human PYRIN and HIN-200 domains (PYHIN) protein family members were initially proposed to be PRRs, although this view has been challenged by reports that revealed their impact on other cellular mechanisms. Of relevance here, the human PYHIN factor myeloid nuclear differentiation antigen (MNDA) has recently been shown to directly control the transcription of genes encoding factors that regulate programmed cell death and inflammation. While MNDA is mainly found in the nucleus of leukocytes of both myeloid (neutrophils and monocytes) and lymphoid (B-cell) origin, its subcellular localization has been shown to be modulated in response to genotoxic agents that induce apoptosis and by bacterial constituents, mediators of inflammation. Prior studies have noted the importance of MNDA as a marker for certain forms of lymphoma, and as a clinical prognostic factor for hematopoietic diseases characterized by defective regulation of apoptosis. Abnormal expression of MNDA has also been associated with altered levels of cytokines and other inflammatory mediators. Refining our comprehension of the regulatory mechanisms governing the expression of MNDA and other PYHIN proteins, as well as enhancing our definition of their molecular functions, could significantly influence the management and treatment strategies of numerous human diseases. Here, we review the current state of knowledge regarding PYHIN proteins and their role in innate and adaptive immune responses. Emphasis will be placed on the regulation, function, and relevance of MNDA expression in the control of gene transcription and RNA stability during cell death and inflammation.
在先天免疫反应中，炎症控制至关重要。这种反应是由模式识别受体 (PRR) 检测来自病原体或受损宿主细胞的分子触发的。PRR 随后通过不同的途径启动细胞内信号转导，导致 i) 炎症细胞因子（包括 I 型干扰素 (IFN)）的产生，和 ii) 启动一系列促进即刻宿主反应和适应性免疫反应的事件。最初所有人类 PYRIN 和 HIN-200 结构域 (PYHIN) 蛋白家族成员都被提议为 PRR，尽管有报道称它们对其他细胞机制有影响，这一观点受到了挑战。在这里相关的是，人类 PYHIN 因子髓样核分化抗原 (MNDA) 最近被证明可以直接控制编码调节程序性细胞死亡和炎症的因子的基因转录。虽然 MNDA 主要存在于骨髓（中性粒细胞和单核细胞）和淋巴（B 细胞）来源的白细胞核中，但已证明其亚细胞定位可响应诱导细胞凋亡的遗传毒性剂和细菌成分（炎症介质）进行调节。先前的研究已经注意到 MNDA 作为某些淋巴瘤形式的标志物的重要性，以及作为特征为凋亡调节缺陷的造血疾病的临床预后因素的重要性。MNDA 的异常表达也与细胞因子和其他炎症介质水平的改变有关。深入了解调节 MNDA 和其他 PYHIN 蛋白表达的调控机制，并增强对其分子功能的定义，可能会对多种人类疾病的管理和治疗策略产生重大影响。在这里，我们回顾了关于 PYHIN 蛋白及其在先天和适应性免疫反应中的作用的现有知识状态。重点将放在 MNDA 表达的调节、功能和相关性上，以控制细胞死亡和炎症过程中的基因转录和 RNA 稳定性。
