HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation.
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DOI：
10.1172/jci153153
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发表时间：
2022-05-02
影响因子：
15.9
通讯作者：
Klein, Christoph
中科院分区：
文献类型：
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作者：
Fan, Yanxin;Murgia, Marta;Linder, Monika, I;Mizoguchi, Yoko;Wang, Cong;Lyszkiewicz, Marcin;Zietara, Natalia;Liu, Yanshan;Frenz, Stephanie;Sciuccati, Gabriela;Partida-Gaytan, Armando;Alizadeh, Zahra;Rezaei, Nima;Rehling, Peter;Dennerlein, Sven;Mann, Matthias;Klein, Christoph
控制线粒体蛋白质稳态的分子机制与造血细胞和免疫细胞的分化和功能的相关性在很大程度上是难以捉摸的。通过对与HCLS 1相关蛋白X-1相关的蛋白质网络的解剖，我们定义了一个潜在的新的功能性CLPB/HAX 1/（PRKD 2）/HSP 27轴，该轴对中性粒细胞的分化至关重要，从而阐明了HAX 1缺乏症患者先天性中性粒细胞减少症的分子和代谢机制以及CLPB中的双等位基因和单等位基因突变。如通过细胞培养物中氨基酸的稳定同位素标记（SILAC）蛋白质组学所示，CLPB和HAX 1控制线粒体蛋白质合成的平衡和对于适当的线粒体功能至关重要的持久性。受损的线粒体蛋白动力学与丝氨酸-苏氨酸激酶PRKD 2和丝氨酸78和82上磷酸化的HSP 27丰度降低相关。HAX 1-/-细胞中的细胞缺陷可以通过HSP 27功能性地重建。因此，线粒体蛋白质稳态成为控制中性粒细胞分化和功能的关键分子和代谢机制。
The relevance of molecular mechanisms governing mitochondrial proteostasis to the differentiation and function of hematopoietic and immune cells is largely elusive. Through dissection of the network of proteins related to HCLS1-associated protein X-1, we defined a potentially novel functional CLPB/HAX1/(PRKD2)/HSP27 axis with critical importance for the differentiation of neutrophil granulocytes and, thus, elucidated molecular and metabolic mechanisms underlying congenital neutropenia in patients with HAX1 deficiency as well as bi- and monoallelic mutations in CLPB. As shown by stable isotope labeling by amino acids in cell culture (SILAC) proteomics, CLPB and HAX1 control the balance of mitochondrial protein synthesis and persistence crucial for proper mitochondrial function. Impaired mitochondrial protein dynamics are associated with decreased abundance of the serine-threonine kinase PRKD2 and HSP27 phosphorylated on serines 78 and 82. Cellular defects in HAX1–/– cells can be functionally reconstituted by HSP27. Thus, mitochondrial proteostasis emerges as a critical molecular and metabolic mechanism governing the differentiation and function of neutrophil granulocytes.