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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Cisd2 deficiency impairs neutrophil function by regulating calcium homeostasis via Calnexin and SERCA

  • Un Yung Choi (Department of Microbiology, Konkuk University School of Medicine) ;
  • Youn Jung Choi (Kao Autoimmunity Institute and Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Center) ;
  • Shin-Ae Lee (Department of Cancer Biology, Infection Biology Program, Global Center for Pathogen and Human Health Research, Lerner Research Institute, Cleveland Clinic) ;
  • Ji-Seung Yoo (School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University)
  • Received : 2024.01.15
  • Accepted : 2024.04.05
  • Published : 2024.05.31
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Abstract

In the context of aging, the susceptibility to infectious diseases increases, leading to heightened morbidity and mortality. This phenomenon, termed immunosenescence, is characterized by dysregulation in the aging immune system, including abnormal alterations in lymphocyte composition, elevated basal inflammation, and the accumulation of senescent T cells. Such changes contribute to increased autoimmune diseases, enhanced infection severity, and reduced responsiveness to vaccines. Utilizing aging animal models becomes imperative for a comprehensive understanding of immunosenescence, given the complexity of aging as a physiological process in living organisms. Our investigation focuses on Cisd2, a causative gene for Wolfram syndrome, to elucidate on immunosenescence. Cisd2 knockout (KO) mice, serving as a model for premature aging, exhibit a shortened lifespan with early onset of aging-related features, such as decreased bone density, hair loss, depigmentation, and optic nerve degeneration. Intriguingly, we found that the Cisd2 KO mice present a higher number of neutrophils in the blood; however, isolated neutrophils from these mice display functional defects. Through mass spectrometry analysis, we identified an interaction between Cisd2 and Calnexin, a protein known for its role in protein quality control. Beyond this function, Calnexin also regulates calcium homeostasis through interaction with sarcoendoplasmic reticulum calcium transport ATPase (SERCA). Our study proposes that Cisd2 modulates calcium homeostasis via its interaction with Calnexin and SERCA, consequently influencing neutrophil functions.

Keywords

Acknowledgement

We thank Dr. Samad Amini-Bavil-Olyaee for initiating the current work. We also thank Dr. Ting-Fen Tsai and Jae U. Jung for providing reagents. This paper was supported by Konkuk University in 2023.

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