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

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

doi:10.1074/jbc.ra118.005865

Cited by 25 publications

(22 citation statements)

References 93 publications

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“… 75 76 Recently, it was reported that ceramide binds to RIPK1 and forms large membrane pores named ceramidosomes, leading to necroptosis induction in A549 human lung cancer cells treated with the sphingolipid analog FTY720. 77 In addition, exogenous ceramide nanoliposome treatment induced MLKL oligomerization and necroptosis in SKOV3 ovarian cancer cells. 78 Therefore, ceramide was also implicated in necroptosis induction.…”

Section: Signal Transduction Is Regulated By Sms-mediated Ceramide/smmentioning

confidence: 98%

Ceramide/Sphingomyelin Rheostat Regulated by Sphingomyelin Synthases and Chronic Diseases in Murine Models

Taniguchi

Okazaki

2020

J Lipid Atheroscler

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Ceramide and sphingomyelin (SM) are major components of the double membranebound sphingolipids. Ceramide is an essential bioactive lipid involved in numerous cell processes including apoptosis, necrosis, and autophagy-dependent cell death. Inversely, SM regulates opposite cellular processes such as proliferation and migration by changing receptor-mediated signal transduction in the lipid microdomain. SM is generated through a transfer of phosphocholine from phosphatidylcholine to ceramide by SM synthases (SMSs). Research during the past several decades has revealed that the ceramide/SM balance in cellular membranes regulated by SMSs is important to decide the cell fate, survival, and proliferation. In addition, recent experimental studies utilizing SMS knockout mice and murine disease models provide evidence that SMS-regulated ceramide/SM balance is involved in human diseases. Here, we review the basic structural and functional characteristics of SMSs and focus on their cellular functions through the regulation of ceramide/SM balance in membrane microdomains. In addition, we present the pathological or physiological implications of SMSs by analyzing their role in SMS-knockout mice and human disease models. This review finally presents evidence indicating that the regulation of ceramide/SM balance through SMS could be a therapeutic target for human disorders.

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Section: Signal Transduction Is Regulated By Sms-mediated Ceramide/smmentioning

confidence: 98%

Ceramide/Sphingomyelin Rheostat Regulated by Sphingomyelin Synthases and Chronic Diseases in Murine Models

Taniguchi

Okazaki

2020

J Lipid Atheroscler

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“…Given the dramatic changes that occur in cell membranes during necroptosis, several research groups have considered lipids to participate and have important roles in this process. Recently, emerging evidence has suggested the significance of lipidic molecules (fatty acids [42], sphingolipids [20,43,44], and glycerophospholipids [14,15]) in the regulation of necroptotic cell death. In addition, lipid rafts have been proposed to play an essential role in the necroptotic cell death pathway [25].…”

Section: Lipidsmentioning

confidence: 99%

“…In 2014, Wang and colleagues showed for the first time that short-chain ceramide (C 2 -ceramide) induced programmed necrosis [51]; however, the molecular mechanism has yet to be elucidated. Ogretmen's group proposed that ceramide and RIPK1 form a complex that assembles a large membrane pore (named ceramidosome), which is responsible for blebbing and necroptosis [44]. Zhang et al discovered that liposomal ceramides facilitated MLKL oligomerization responsible for necroptosis [20].…”

Section: Ceramidementioning

confidence: 99%

“…However, whether FTY720-induced PP2A activation directly regulates RIPK1 for the induction of necroptosis remains unknown. Moreover, recent advances suggest that FTY720 promotes the formation of C 16 -ceramide-and RIPK1-enriched membrane pores, referred to as ceramidosomes [44], which likely regulate membrane integrity and signaling in necroptosis.…”

Section: Sphingosine Analogue Fty720 (Fingolimod)mentioning

confidence: 99%

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Regulation of Necroptosis by Phospholipids and Sphingolipids

Zhang

Matsuda

Yaegashi

et al. 2020

Cells

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Several non-apoptotic regulated cell death pathways have been recently reported. Necroptosis, a form of necrotic-regulated cell death, is characterized by the involvement of receptor-interacting protein kinases and/or the pore-forming mixed lineage kinase domain-like protein. Recent evidence suggests a key role for lipidic molecules in the regulation of necroptosis. The purpose of this mini-review is to outline the regulation of necroptosis by sphingolipids and phospholipids.

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“…The acyl chain of C 16 -ceramide has recently been shown to specifically impact cellular processes. For example, C 16 -ceramide directly binds to RIPK1, which leads to the formation of ceramidosomes during necroptosis 41 . C 16 -ceramide also directly binds to p53, thereby disrupting the interaction of the E3 ligase MDM2, which results in p53 accumulation 42 .…”

mentioning

confidence: 99%

Expression of the SNAI2 transcriptional repressor is regulated by C₁₆-ceramide

Lü

White‐Gilbertson

Nganga

et al. 2019

Cancer Biology & Therapy

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Ceramide synthase 6 (CerS6) is an enzyme that preferentially generates pro-apoptotic C 16-ceramide in the sphingolipid metabolic pathway. Reduced expression of CerS6 has been associated with apoptosis resistance and recent studies point to a role for CerS6 in epithelial mesenchymal transition (EMT). Because cells that undergo EMT are also more resistant to apoptosis, we hypothesized that reduced expression of CerS6 could induce changes that are associated with EMT. We found that shRNA-mediated knockdown of CerS6 increases expression of the EMT transcription factor SNAI2 but not SNAI1 or TWIST. Treatment with C 6ceramide nanoliposomes (CNL) resulted in a preferential increase in C 16-ceramide and suppressed SNAI2 transcriptional activation and protein expression. The increase in C 16-ceramide following CNL treatment was dependent on CerS activity and occurred even when CerS6 shRNA was expressed. shRNA against CerS5, which like CerS6 preferentially generates C 16-ceramide, also decreased transcriptional activation of SNAI2, suggesting a role for C 16-ceramide rather than a specific enzyme in the regulation of this transcription factor. While loss of CerS6 has been associated with apoptosis resistance, we found that cells lacking this protein are more susceptible to the effects CNL. In summary, our study identifies SNAI2 as a novel target whose expression can be influenced by C 16-ceramide levels. The potential of CNL to suppress SNAI2 expression has important clinical implications, since elevated expression of this transcription factor has been associated with an aggressive phenotype or poor outcomes in several types of solid tumors.

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

Cited by 25 publications

References 93 publications

Ceramide/Sphingomyelin Rheostat Regulated by Sphingomyelin Synthases and Chronic Diseases in Murine Models

Ceramide/Sphingomyelin Rheostat Regulated by Sphingomyelin Synthases and Chronic Diseases in Murine Models

Regulation of Necroptosis by Phospholipids and Sphingolipids

Expression of the SNAI2 transcriptional repressor is regulated by C₁₆-ceramide

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

Cited by 25 publications

References 93 publications

Ceramide/Sphingomyelin Rheostat Regulated by Sphingomyelin Synthases and Chronic Diseases in Murine Models

Ceramide/Sphingomyelin Rheostat Regulated by Sphingomyelin Synthases and Chronic Diseases in Murine Models

Regulation of Necroptosis by Phospholipids and Sphingolipids

Expression of the SNAI2 transcriptional repressor is regulated by C16-ceramide

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Expression of the SNAI2 transcriptional repressor is regulated by C₁₆-ceramide