Receptor-interacting Ser/Thr kinase 1 (RIPK1) and myosin IIA– dependent ceramidosomes form membrane pores that mediate blebbing and necroptosis

Rose Nganga, Natalia Oleinik, Jisun Kim, Shanmugam Panneer Selvam, Ryan De Palma, Kristen A. Johnson, Rasesh Y. Parikh, Vamsi Gangaraju, Yuri Peterson, Mohammed Dany, Robert V. Stahelin, Christina Voelkel-Johnson, Zdzislaw M. Szulc, Erhard Bieberich, Besim Ogretmen

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Formation of membrane pores/channels regulates various cellular processes, such as necroptosis or stem cell niche signaling. However, the roles of membrane lipids in the formation of pores and their biological functions are largely unknown. Here, using the cellular stress model evoked by the sphingolipid analog drug FTY720, we show that formation of ceramide-enriched membrane pores, referred to here as ceramidosomes, is initiated by a receptor-interacting Ser/Thr kinase 1 (RIPK1)– ceramide complex transported to the plasma membrane by nonmuscle myosin IIA– dependent trafficking in human lung cancer cells. Molecular modeling/simulation coupled with site-directed mutagenesis revealed that Asp147 or Asn169 of RIPK1 are key for ceramide binding and that Arg258 or Leu293 residues are involved in the myosin IIA interaction, leading to ceramidosome formation and necroptosis. Moreover, generation of ceramidosomes independently of any external drug/stress stimuli was also detected in the plasma membrane of germ line stem cells in ovaries during the early stages of oogenesis in Drosophila melanogaster. Inhibition of ceramidosome formation via myosin IIA silencing limited germ line stem cell signaling and abrogated oogenesis. In conclusion, our findings indicate that the RIPK1– ceramide complex forms large membrane pores we named ceramidosomes. They further suggest that, in addition to their roles in stress-mediated necroptosis, these ceramide-enriched pores also regulate membrane integrity and signaling and might also play a role in D. melanogaster ovary development.

Original languageEnglish (US)
Pages (from-to)502-519
Number of pages18
JournalJournal of Biological Chemistry
Volume294
Issue number2
DOIs
StatePublished - Jan 11 2019
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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