HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation

Fan, Yanxin; Murgia, Marta; Linder, Monika; 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 und Klein, Christoph (2022): HAX1-dependent control of mitochondrial proteostasis governs neutrophil granulocyte differentiation. In: Journal of Clinical Investigation, Bd. 132, Nr. 9

Abstract

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 HCLS1associated 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0021-9738
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390729940