Tehran University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share this content! On (X network) By
Hax1-Dependent Control of Mitochondrial Proteostasis Governs Neutrophil Granulocyte Differentiation Publisher Pubmed



Fan Y1 ; Murgia M2, 3 ; Linder MI1 ; Mizoguchi Y1 ; Wang C4 ; Lyszkiewicz M1 ; Zietara N1 ; Liu Y1 ; Frenz S1 ; Sciuccati G5 ; Partidagaytan A6 ; Alizadeh Z7 ; Rezaei N8 ; Rehling P4, 9, 10 Show All Authors
Authors
  1. Fan Y1
  2. Murgia M2, 3
  3. Linder MI1
  4. Mizoguchi Y1
  5. Wang C4
  6. Lyszkiewicz M1
  7. Zietara N1
  8. Liu Y1
  9. Frenz S1
  10. Sciuccati G5
  11. Partidagaytan A6
  12. Alizadeh Z7
  13. Rezaei N8
  14. Rehling P4, 9, 10
  15. Dennerlein S4
  16. Mann M2
  17. Klein C1
Show Affiliations
Authors Affiliations
  1. 1. Department of Pediatrics, Dr. von Hauner Children’s Hospital and Gene Center, University Hospital, Ludwig-Maximilians-Universitat (LMU), Munich, Germany
  2. 2. Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany
  3. 3. Department of Biomedical Sciences, University of Padua, Padua, Italy
  4. 4. Department of Cellular Biochemistry, University Medical Center Goettingen, Goettingen, Germany
  5. 5. Hematology and Oncology Department, Hospital de Pediatria “Prof. Dr. J.P. Garrahan, Buenos Aires, Argentina
  6. 6. Unidad de Investigacion en Inmunodeficiencias Primarias, Instituto Nacional de Pediatria, Mexico City, Mexico
  7. 7. Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran
  8. 8. Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  9. 9. Cluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells, �, University of Goettingen, Goettingen, Germany
  10. 10. Max Planck Institute for Biophysical Chemistry, Goettingen, Germany

Source: Journal of Clinical Investigation Published:2022


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 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. 2022, Fan et al.
Related Docs
1. In Vitro Study of Hax1 Gene Therapy by Retro Viral Transduction As a Therapeutic Target in Severe Congenital Neutropenia, European Cytokine Network (2018)
2. Human Genetic Defects in Srp19 and Srpra Cause Severe Congenital Neutropenia With Distinctive Proteome Changes, Blood (2023)
3. Evaluation of the Effects of Mesenchymal Stem Cells on Neutrophils Isolated From Severe Congenital Neutropenia Patients, International Immunopharmacology (2020)
4. Structure and Function of the Immune System, Encyclopedia of Infection and Immunity (2022)
Experts (# of related papers)
View all Related Experts
Nima Rezaei (4)
Farzad Kompani (1)