GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway

Park A. Y., Leney-Greene M., Lynberg M., Gabrielski J. Q., Xu X., Schwarz B., ...Daha Fazla

Nature Immunology, cilt.25, sa.2, ss.282-293, 2024 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 25 Sayı: 2
  • Basım Tarihi: 2024
  • Doi Numarası: 10.1038/s41590-023-01691-y
  • Dergi Adı: Nature Immunology
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, Food Science & Technology Abstracts, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.282-293
  • Marmara Üniversitesi Adresli: Evet

Özet

Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals.